Macrocyclic sulfondiimine compounds

ABSTRACT

The present invention relates to novel macrocyclic sulfondiimine compounds of general formula (I) as described and defined herein, and methods for their preparation, their use for the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Phase application under 35 U.S.C. § 371of International Application No. PCT/EP2016/072795, filed Sep. 26, 2016,which claims priority benefit of Chinese Application No.PCT/CN2015/091056, filed Sep. 29, 2015.

The present invention relates to novel macrocyclic sulfondiiminecompounds of general formula (I) as described and defined herein, andmethods for their preparation, their use for the treatment and/orprophylaxis of disorders, in particular of hyper-proliferative disordersand/or virally induced infectious diseases and/or of cardiovasculardiseases. The invention further relates to intermediate compounds usefulin the preparation of said compounds of general formula (I).

The family of cyclin-dependent kinase (CDK) proteins consists of membersthat are key regulators of the cell division cycle (cell cycle CDK's),that are involved in regulation of gene transcription (transcriptionalCDK's), and of members with other functions. CDKs require for activationthe association with a regulatory cyclin subunit. The cell cycle CDKsCDK1/cyclin B, CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, andCDK6/cyclinD get activated in a sequential order to drive a cell intoand through the cell division cycle. The transcriptional CDKsCDK9/cyclin T and CDK7/cyclin H regulate the activity of RNApolymeraseII via phosphorylation of the carboxy-terminal domain (CTD). Positivetranscription factor b (P-TEFb) is a heterodimer of CDK9 and one of fourcyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b.

Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved intranscriptional regulation, CDK7 in addition participates in cell cycleregulation as CDK-activating kinase (CAK). Transcription of genes by RNApolymerase II is initiated by assembly of the pre-initiation complex atthe promoter region and phosphorylation of Ser 5 and Ser 7 of the CTD byCDK7/cyclin H. For a major fraction of genes RNA polymerase II stopsmRNA transcription after it moved 20-40 nucleotides along the DNAtemplate. This promoter-proximal pausing of RNA polymerase II ismediated by negative elongation factors and is recognized as a majorcontrol mechanism to regulate expression of rapidly induced genes inresponse to a variety of stimuli (Cho et al., Cell Cycle 9, 1697, 2010).P-TEFb is crucially involved in overcoming promoter-proximal pausing ofRNA polymerase II and transition into a productive elongation state byphosphorylation of Ser 2 of the CTD as well as by phosphorylation andinactivation of negative elongation factors.

Activity of PTEFb itself is regulated by several mechanisms. About halfof cellular PTEFb exists in an inactive complex with 7SK small nuclearRNA (7SK snRNA), La-related protein 7 (LARP7/PIP7S) and hexamethylenebis-acetamide inducible proteins 1/2 (HEXIM1/2, He et al., Mol Cell 29,588, 2008). The remaining half of PTEFb exists in an active complexcontaining the bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535,2005). Brd4 recruits PTEFb through interaction with acetylated histonesto chromatin areas primed for gene transcription. Through alternatelyinteracting with its positive and negative regulators, PTEFb ismaintained in a functional equilibrium: PTEFb bound to the 7SK snRNAcomplex represents a reservoir from which active PTEFb can be releasedon demand of cellular transcription and cell proliferation (Zhou & Yik,Microbiol Mol Biol Rev 70, 646, 2006). Furthermore, the activity ofPTEFb is regulated by posttranslational modifications includingphosphorylation/de-phosphorylation, ubiquitination, and acetylation(reviewed in Cho et al., Cell Cycle 9, 1697, 2010).

Deregulated activity of CDK9 kinase activity of the PTEFb heterodimer isassociated with a variety of human pathological settings such ashyper-proliferative diseases (e.g. cancer), virally induced infectiousdiseases or cardiovascular diseases:

Cancer is regarded as a hyper-proliferative disorder mediated by adisbalance of proliferation and cell death (apoptosis). High levels ofanti-apoptotic Bcl-2-family proteins are found in various human tumorsand account for prolonged survival of tumor cells and therapyresistance. Inhibition of PTEFb kinase activity was shown to reducetranscriptional activity of RNA polymerase II leading to a decline ofshort-lived anti-apoptotic proteins, especially Mcl-1 and XIAP,reinstalling the ability of tumor cells to undergo apoptosis. A numberof other proteins associated with the transformed tumor phenotype (suchas Myc, NF-kB responsive gene transcripts, mitotic kinases) are eithershort-lived proteins or are encoded by short-lived transcripts which aresensitive to reduced RNA polymerase II activity mediated by PTEFbinhibition (reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302,2008).

Many viruses rely on the transcriptional machinery of the host cell forthe transcription of their own genome. In case of HIV-1, RNA polymeraseII gets recruited to the promoter region within the viral LTR's. Theviral transcription activator (Tat) protein binds to nascent viraltranscripts and overcomes promoter-proximal RNA polymerase II pausing byrecruitment of PTEFb which in turn promotes transcriptional elongation.Furthermore, the Tat protein increases the fraction of active PTEFb byreplacement of the PTEFb inhibitory proteins HEXIM1/2 within the 7SKsnRNA complex. Recent data have shown that inhibition of the kinaseactivity of PTEFb is sufficient to block HIV-1 repliction at kinaseinhibitor concentrations that are not cytotoxic to the host cells(reviewed in Wang & Fischer, Trends Pharmacol Sci 29, 302, 2008).Similarly, recruitment of PTEFb by viral proteins has been reported forother viruses such as B-cell cancer-associated Epstein-Barr virus, wherethe nuclear antigen EBNA2 protein interacts with PTEFb (Bark-Jones etal., Oncogene, 25, 1775, 2006), and the human T-lymphotropic virus type1 (HTLV-1), where the transcriptional activator Tax recruits PTEFb (Zhouet al., J Virol. 80, 4781, 2006).

Cardiac hypertrophy, the heart's adaptive response to mechanicaloverload and pressure (hemodynamic stress e.g. hypertension, myocardialinfarction), can lead, on a long term, to heart failure and death.Cardiac hypertrophy was shown to be associated with increasedtranscriptional activity and RNA polymerase II CTD phosphorylation incardiac muscle cells. PTEFb was found to be activated by dissociationfrom the inactive 7SK snRNA/HEXIM1/2 complex. These findings suggestpharmacological inhibition of PTEFb kinase activity as a therapeuticapproach to treat cardiac hypertrophy (reviewed in Dey et al., CellCycle 6, 1856, 2007).

In summary, multiple lines of evidence suggest that selective inhibitionof the CDK9 kinase activity of the PTEFb heterodimer (=CDK9 and one offour cyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b) representsan innovative approach for the treatment of diseases such as cancer,viral diseases, and/or diseases of the heart. CDK9 belongs to a familyof at least 13 closely related kinases of which the subgroup of the cellcycle CDK's fulfills multiple roles in regulation of cell proliferation.Thus, co-inhibition of cell cycle CDKs (e.g. CDK1/cyclin B, CDK2/cyclinA, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of CDK9, is expected toimpact normal proliferating tissues such as intestinal mucosa, lymphaticand hematopoietic organs, and reproductive organs. To maximize thetherapeutic value of CDK9 kinase inhibitors, molecules with improvedduration of action and/or high potency and efficacy and/or selectivitytowards CDK9 are required.

CDK inhibitors in general as well as CDK9 inhibitors are described in anumber of different publications: WO2008129070 and WO2008129071 bothdescribe 2,4 disubstituted aminopyrimidines as CDK inhibitors ingeneral. It is also asserted that some of these compounds may act asselective CDK9 inhibitors (WO2008129070) and as CDK5 inhibitors(WO02008129071), respectively, but no specific CDK9 IC₅₀ (WO2008129070)or CDK5 IC₅₀ (WO2008129071) data is presented. These compounds do notcontain a fluorine atom in 5-position of the pyrimidine core.

WO2008129080 discloses 4,6 disubstituted aminopyrimidines anddemonstrates that these compounds show an inhibitory effect on theprotein kinase activity of various protein kinases, such as CDK1, CDK2,CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9 inhibition(example 80).

WO2005026129 discloses 4,6 disubstituted aminopyrimidines anddemonstrates that these compounds show an inhibitory effect on theprotein kinase activity of various protein kinases, in particular CDK2,CDK4, and CDK9.

WO 2009118567 discloses pyrimidine and [1,3,5]triazine derivatives asprotein kinase inhibitors, in particular CDK2, CDK7 and CDK9.

WO02011116951 discloses substituted triazine derivatives as selectiveCDK9 inhibitors.

WO2012117048 discloses disubstituted triazine derivatives as selectiveCDK9 inhibitors.

WO02012117059 discloses disubstituted pyridine derivatives as selectiveCDK9 inhibitors.

WO02012143399 discloses substituted4-aryl-N-phenyl-1,3,5-triazin-2-amines as selective CDK9 inhibitors.

EP1218360 B1, which corresponds to US2004116388A1, U.S. Pat. No.7,074,789B2 and WO2001025220A1, describes triazine derivatives as kinaseinhibitors, but does not disclose potent or selective CDK9 inhibitors.

WO02008079933 discloses aminopyridine and aminopyrimidine derivativesand their use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9inhibitors.

WO2011012661 describes aminopyridine derivatives useful as CDKinhibitors.

WO2011026917 discloses carboxamides derived from substituted4-phenylpyridine-2-amines as inhibitors of CDK9.

WO2012066065 discloses phenyl-heterorayl amines as inhibitors of CDK9. Aselectivity towards CDK9 over other CDK isoforms is preferred, howeverdisclosure of CDK-inhibition data is confined to CDK 9. No bicyclic ringsystems are disclosed attached to the C4 position of the pyrimidinecore. Within the group attached to C4 of the pyrimidine core, alkoxyphenyls can be regarded as encompassed, but there is no suggestion for aspecific substitution pattern characterised by a fluorine atom attachedto C5 of the pyrimidine ring, and an aniline at C2 of the pyrimidine,featuring a substituted sulfonyl-methylene group in meta position.Compounds shown in the examples typically feature a substitutedcycloalkyl group as R¹ but no phenyl.

WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as inhibitors ofCDK9. The biaryl core mandatorily consists of two heteroaromatic rings.

WO2012101062 discloses substituted bi-heteroaryl compounds featuring a2-aminopyridine core as inhibitors of CDK9. The biaryl core mandatorilyconsists of two heteroaromatic rings.

WO2012101063 discloses carboxamides derived from substituted4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.

WO 2012101064 discloses N-acyl pyrimidine biaryl compounds as inhibitorsof CDK9.

WO 2012101065 discloses pyrimidine biaryl compounds as inhibitors ofCDK9. The biaryl core mandatorily consists of two heteroaromatic rings.

WO 2012101066 discloses pyrimidine biaryl compounds as inhibitors ofCDK9. Substitution R¹ of the amino group attached to the heteroaromaticcore is confined to non-aromatic groups but does not cover substitutedphenyls. Furthermore, the biaryl core mandatorily consists of twoheteroaromatic rings.

WO 2011077171 discloses 4,6-disubstituted aminopyrimidine derivatives asinhibitors of CDK9.

WO 2014031937 discloses 4,6-disubstituted aminopyrimidine derivatives asinhibitors of CDK9.

WO 2013037896 discloses disubstituted 5-fluoropyrimidines as selectiveinhibitors of CDK9.

WO 2013037894 discloses disubstituted 5-fluoropyrimidine derivativescontaining a sulfoximine group as selective inhibitors of CDK9.

Wang et al. (Chemistry & Biology 17, 1111-1121, 2010) describe2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors,which show anticancer activity in animal models.

WO 2014060376 discloses substituted4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivativescontaining a sulfone group as selective inhibitors of CDK9.

WO 2014060375 discloses substituted5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing asulfone group as selective inhibitors of CDK9.

WO 2014060493 discloses substituted N-(pyridin-2-yl)pyrimidin-4-aminederivatives containing a sulfone group as selective inhibitors of CDK9.

WO 2014076028 discloses substituted4-(ortho)-fluorophenyl-5-fluoropyrimidin-2-yl amine derivativescontaining a sulfoximine group as selective inhibitors of CDK9.

WO 2014076091 discloses substituted5-fluoro-N-(pyridin-2-yl)pyridin-2-amine derivatives containing asulfoximine group as selective inhibitors of CDK9.

WO 2014076111 discloses substituted N-(pyridin-2-yl)pyrimidin-4-aminederivatives containing a sulfoximine group as selective inhibitors ofCDK9.

WO 2015001021 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-aminederivatives containing a sulfoximine group as selective inhibitors ofCDK9.

WO 2015136028 discloses 5-fluoro-N-(pyridin-2-yl)pyridin-2-aminederivatives containing a sulfone group as selective inhibitors of CDK9.

WO2004009562 discloses substituted triazine kinase inhibitors. Forselected compounds CDK1 and CDK4 test data, but no CDK9 data ispresented.

WO2004072063 describes heteroaryl (pyrimidine, triazine) substitutedpyrroles as inhibitors of protein kinases such as ERK2, GSK3, PKA orCDK2.

WO02010009155 discloses triazine and pyrimidine derivatives asinhibitors of histone deacetylase and/or cyclin dependent kinases(CDKs). For selected compounds CDK2 test data is described.

WO2003037346 (corresponding to U.S. Pat. No. 7,618,968B2, U.S. Pat. No.7,291,616B2, US2008064700A1, US2003153570A1) relates to aryl triazinesand uses thereof, including to inhibit lysophosphatidic acidacyltransferase beta (LPAAT-beta) activity and/or proliferation of cellssuch as tumor cells.

WO2005037800 discloses sulfoximine substituted anilino-pyrimidines asinhibitors of VEGFR and CDK kinases, in particular VEGFR2, CDK1 andCDK2, having no aromatic ring directly bonded to the pyrimidine ring andhaving the sulfoximine group directly bonded to the aniline group. NoCDK9 data are disclosed.

WO2008025556 describes carbamoyl sulfoximides having a pyrimidine core,which are useful as kinase inhibitors. No CDK9 data is presented. Nomolecules are exemplified, which possess a fluoropyrimidine core.

WO02002066481 describes pyrimidine derivatives as cyclin dependentkinase inhibitors. CDK9 is not mentioned and no CDK9 data is presented.

WO2008109943 concerns phenyl aminopyri(mi)dine compounds and their useas kinase inhibitors, in particular as JAK2 kinase inhibitors. Thespecific examples mainly focus on compounds having a pyrimidine core.

WO2009032861 describes substituted pyrimidinyl amines as JNK kinaseinhibitors. The specific examples mainly focus on compounds having apyrimidine core.

WO02011046970 concerns amino-pyrimidine compounds as inhibitors of TBK1and/or IKK epsilon. The specific examples mainly focus on compoundshaving a pyrimidine core.

WO2012142329 concerns amino-pyrimidine compounds as inhibitors of TBK1and/or IKK epsilon.

WO2012139499 discloses urea substituted anilino-pyrimidines asinhibitors of various protein kinases.

WO2014106762 discloses 4-pyrimidinylamino-benzenesulfonamide derivativesas inhibitors of polo-like kinase-1.

Macrocyclic compounds have been described as therapeutically usefulsubstances, in particular of various protein kinases including cyclindependent kinases. However, the documents listed below do not disclosespecific compounds as inhibitors of CDK9.

WO 2007147574 discloses sulfonamido-macrocycles as inhibitors of Tie2showing selectivity over CDK2 and Aurora kinase C, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO 2007147575 discloses further sulfonamido-macrocycles as inhibitors ofTie2 and KDR showing selectivity over CDK2 and Plk1, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO 2006066957/EP 1674470 discloses further sulfonamido-macrocycles asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO 2006066956/EP 1674469 discloses further sulfonamido-macrocycles asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO 2004026881/DE 10239042 discloses macrocyclic pyrimidine derivativesas inhibitors of cyclin dependent kinases, in particular CDK1 and CDK2,as well as VEGF-R, inter alia for the treatment of cancer. The compoundsof the present invention differ from those disclosed in WO 2004026881 infeaturing a mandatory biaromatic portion within the macrocyclic ringsystem. Furthermore, none of the example compounds disclosed in WO2004026881 features a sulfondiimine group.

WO 2007079982/EP 1803723 discloses macrocyclic benzenacyclononaphanes asinhibtors of multiple protein kinases, e.g. Aurora kinases A and C,CDK1, CDK2 and c-Kit, inter alia for the treatment of cancer. Thecompounds of the present invention differ from those disclosed in WO2007079982 in featuring a mandatory biaromatic portion within themacrocyclic ring system. Furthermore, the compounds of the presentinvention do not feature a sulfondiimine group.

WO 2006106895/EP 1710246 discloses sulfoximine-macrocycle compounds asinhibitors of Tie2 showing low cytotoxicity, inter alia for thetreatment of diseases accompanied with dysregulated vascular growth.

WO 2012009309 discloses macrocyclic compounds fused to benzene andpyridine rings for the reduction of beta-amyloid production.

WO 2009132202 discloses macrocyclic compounds as inhibitors of JAK 1, 2and 3, TYK2 and ALK and their use in the treatment of JAK/ALK-associateddiseases, including inflammatory and autoimmune disease as well ascancer.

ChemMedChem 2007, 2(1), 63-77 describes macrocyclic aminopyrimidines asmultitarget CDK and VEGF-R inhibitors with potent antiproliferativeactivity. The compounds of the present invention differ from thosedisclosed in said journal publication in featuring a mandatorybiaromatic portion within the macrocyclic ring system. Furthermore, noneof the compounds disclosed in ChemMedChem 2007, 2(1), 63-77 features asulfondiimine group.

Sulfondiimines are high-valent sulphur compounds first described byColiano and Braude in 1964 (J. A. Cogliano, G. L. Braude, J. Org. Chem.1964, 29, 1397), and since their discovery, they have received onlyminimal interest in the scientific community (M. Candy, R. A. Bohmann,C. Bolm, Adv. Synth. Catal. 2012, 354, 2928). Thus, there are only veryfew examples for the use of the sulfondiimine group in medicinalchemistry approaches (see for example a) DE2520230, Ludwig Heumann & Co.GmbH; b) W. L. Mock, J.-T. Tsay, J. Am. Chem. Soc. 1989, 111, 4467).

Despite the fact that various inhibitors of CDKs are known, thereremains a need for selective CDK9 inhibitors, especially CDK9 inhibitorswhich are selective at high ATP concentrations, to be used for thetreatment of diseases such as hyper-proliferative diseases, viraldiseases, and/or diseases of the heart, which offer one or moreadvantages over the compounds known from prior art, such as:

-   -   improved activity and/or efficacy, allowing e.g. a dose        reduction    -   improved side effect profile, such as fewer undesired side        effects, lower intensity of side effects, or reduced        (cyto)toxicity    -   improved duration of action, e.g. by improved pharmacokinetics        and/or improved target residence time

A particular object of the invention is to provide selective CDK9 kinaseinhibitors, which show an improved anti-proliferative activity in tumorcell lines, such as HeLa, HeLa-MaTu-ADR, NCI—H460, DU145, Caco-2,B16F10, A2780 or MOLM-13, compared to compounds known from prior art.

Another object of the invention is to provide selective CDK9 kinaseinhibitors which show an increased potency to inhibit CDK9 activity(demonstrated by a lower IC₅₀ value for CDK9/Cyclin T1) compared to thecompounds known from prior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an increased potency to inhibit CDK9activity at high ATP concentrations compared to compounds known fromprior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an increased target residence time comparedto compounds known from prior art.

Another particular object of the invention is to provide selective CDK9kinase inhibitors which show an improved duration of action, e.g. byimproved pharmacokinetics and/or improved target residence time.

Further, it is an object of the present invention to provide selectiveCDK9 kinase inhibitors, which, compared to the compounds known fromprior art, show an improved anti-proliferative activity in tumor celllines, such as HeLa, HeLa-MaTu-ADR, NCI—H460, DU145, Caco-2, B16F10,A2780 or MOLM-13, and/or which show an increased potency to inhibit CDK9activity (demonstrated by a lower IC₅₀ value for CDK9/Cyclin T1),especially an increased potency to inhibit CDK9 activity at high ATPconcentrations, and/or which show an increased target residence timecompared to the compounds known from prior art.

The CDK9 kinase inhibitors according to the invention shall havesimultaneously selectivity for CDK9/Cyclin T1 over CDK2/Cyclin E,especially at high ATP concentrations.

The selective CDK9 kinase inhibitors according to the invention shallhave an acceptable CaCo-2 permeability and/or an acceptable CaCo-2efflux ratio, and/or shall show an acceptable aqueous solubility.

The present invention relates to compounds of general formula (I)

-   wherein-   L represents a C₂-C₈-alkylene group, wherein said group is    optionally substituted with    -   (i) one substituent selected from hydroxy, —NR⁶R⁷,        C₂-C₃-alkenyl-, C₂-C₃-alkynyl-, C₃-C₄-cycloalkyl-,        hydroxy-C₁-C₃-alkyl-, —(CH₂)NR⁶R⁷, and/or    -   (ii) one or two or three or four substituents, identically or        differently, selected from halogen and C₁-C₃-alkyl-,    -   with the proviso that a C₂-alkylene group is not substituted        with a hydroxy or a —NR⁶R⁷ group,    -   or wherein    -   one carbon atom of said C₂—C-alkylene group forms a three- or        four-membered ring together with a bivalent group to which it is        attached, wherein said bivalent group is selected from —CH₂CH₂—,        —CH₂CH₂CH₂—, —CH₂OCH₂—;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₆-alkyl-, C₃-C₆-alkenyl-,    C₃-C₆-alkynyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-,    heteroaryl-, phenyl-C₁-C₃-alkyl- and heteroaryl-C₁-C₃-alkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group consisting of hydroxy, cyano, halogen, C₁-C₆-alkyl-,        halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂,        alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH,        —C(═O)NH₂;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-;-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine    atom, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,    C₁-C₃-fluoroalkoxy-;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₆-alkyl-,    C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-, wherein said    C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl- or    heteroaryl-group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,    —NH₂, alkylamino-, dialkylamino-, acetylamino-,    N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,    C₁-C₃-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-,    heterocyclyl-, phenyl-, benzyl- and heteroaryl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,        phenyl-, benzyl- or heteroaryl-group is optionally substituted        with one, two or three substituents, identically or differently,        selected from the group consisting of halogen, hydroxy,        C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        acetylamino-, N-methyl-N-acetylamino-, cyclic amines,        halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R⁸ represents a group selected from C₁-C₆-alkyl-, halo-C₁-C₃-alkyl-,    C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl- and heteroaryl-,    -   wherein said group is optionally substituted with one, two or        three substituents, identically or differently, selected from        the group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,        N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,        C₁-C₃-fluoroalkoxy-,-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds of the hereinafter recited formula which are encompassed byformula (I) and the salts, solvates and solvates of the salts thereof,and the compounds which are encompassed by formula (I) and are mentionedhereinafter as exemplary embodiments and the salts, solvates andsolvates of the salts thereof, where the compounds which are encompassedby formula (I) and are mentioned hereinafter are not already salts,solvates and solvates of the salts.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The invention therefore relates to the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated in a known manner from such mixtures of enantiomersand/or diastereomers.

If the compounds according to the invention can be in tautomeric forms,the present invention encompasses all tautomeric forms.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any physiologically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

Salts which are preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. However, salts which are not suitable for pharmaceuticalapplications per se, but which, for example, can be used for theisolation or purification of the compounds according to the invention,are also comprised.

The term “physiologically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention, for example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

Physiologically acceptable salts of the compounds according to theinvention encompass acid addition salts of mineral acids, carboxylicacids and sulfonic acids, for example salts of hydrochloric acid,hydrobromic acid, hydroiodic, sulfuric acid, bisulfuric acid, sulfamicacid, phosphoric acid, nitric acid or with an organic acid, such asformic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, pivalic,2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, or thiocyanic acid, for example.

Physiologically acceptable salts of the compounds according to theinvention also comprise salts of conventional bases, such as, by way ofexample and by preference, alkali metal salts (for example sodium andpotassium salts), alkaline earth metal salts (for example calcium andmagnesium salts) and ammonium salts derived from ammonia or organicamines with 1 to 16 C atoms, such as, by way of example and bypreference, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine,N-methylpiperidine, N-methylglucamine, dimethylglucamine,ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol,tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol. Additionally, the compounds according to theinvention may form salts with a quarternary ammonium ion obtainable e.g.by quarternisation of a basic nitrogen containing group with agents suchas lower alkylhalides such as methyl-, ethyl-, propyl-, andbutylchlorides, -bromides and -iodides; dialkylsulfates such asdimethyl-, diethyl-, dibutyl- and diamylsulfates, long chain halidessuch as decyl-, lauryl-, myristyl- and stearylchlorides, -bromides and-iodides, aralkylhalides such as benzyl- and phenethylbromides andothers. Examples of suitable quarternary ammonium ions aretetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, or N-benzyl-N,N N-trimethylammonium.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds according to the invention which form a complexwith solvent molecules by coordination in the solid or liquid state.Hydrates are a special form of solvates in which the coordination takesplace with water. Hydrates are preferred as solvates within the scope ofthe present invention.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S,¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

In addition, the present invention also encompasses prodrugs of thecompounds according to the invention. The term “prodrugs” encompassescompounds which themselves may be biologically active or inactive, butare converted (for example by metabolism or hydrolysis) to compoundsaccording to the invention during their residence time in the body.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

Accordingly, the present invention includes all possible salts,polymorphs, metabolites, hydrates, solvates, prodrugs (e.g.: esters)thereof, and diastereoisomeric forms of the compounds of the presentinvention as single salt, polymorph, metabolite, hydrate, solvate,prodrug (e.g.: esters) thereof, or diastereoisomeric form, or as mixtureof more than one salt, polymorph, metabolite, hydrate, solvate, prodrug(e.g.: esters) thereof, or diastereoisomeric form in any ratio.

For the purposes of the present invention, the substituents have thefollowing meaning, unless otherwise specified:

The term “halogen”, “halogen atom” or “halo” represents fluorine,chlorine, bromine and iodine, particularly bromine, chlorine orfluorine, preferably chlorine or fluorine, more preferably fluorine.

The term “alkyl-” represents a linear or branched alkyl-group having thenumber of carbon atoms specifically indicated, e.g. C₁-C₁₀ one, two,three, four, five, six, seven, eight, nine or ten carbon atoms, e.g.methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-,tert-butyl-, pentyl-, isopentyl-, hexyl-, heptyl-, octyl-, nonyl-,decyl-, 2-methylbutyl-, 1-methylbutyl-, 1-ethylpropyl-,1,2-dimethylpropyl-, neo-pentyl-, 1,1-dimethylpropyl-, 4-methylpentyl-,3-methylpentyl-, 2-methylpentyl-, 1-methylpentyl-, 2-ethylbutyl-,1-ethylbutyl-, 3,3-dimethylbutyl-, 2,2-dimethylbutyl-,1,1-dimethylbutyl-, 2,3-dimethylbutyl-, 1,3-dimethylbutyl-, or1,2-dimethylbutyl-. If the number of carbon atoms is not specificallyindicated the term “alkyl-” represents a linear or branched alkyl-grouphaving, as a rule, 1 to 9, particularly 1 to 6, preferably 1 to 4 carbonatoms. Particularly, the alkyl-group has 1, 2, 3, 4, 5 or 6 carbon atoms(“C₁-C₆-alkyl-”), e.g. methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-,tert-butyl-, pentyl-, isopentyl-, hexyl-, 2-methylbutyl-,1-methylbutyl-, 1-ethylpropyl-, 1,2-dimethylpropyl-, neo-pentyl-,1,1-dimethylpropyl-, 4-methylpentyl-, 3-methylpentyl-, 2-methylpentyl-,1-methylpentyl-, 2-ethylbutyl-, 1-ethylbutyl-, 3,3-dimethylbutyl-,2,2-dimethylbutyl-, 1,1-dimethylbutyl-, 2,3-dimethylbutyl-,1,3-dimethylbutyl-, or 1,2-dimethylbutyl-. Preferably, the alkyl-grouphas 1, 2 or 3 carbon atoms (“C₁-C₃-alkyl-”), methyl-, ethyl-, n-propyl-or isopropyl-.

The term “C₂-C₈-alkylene” is to be understood as preferably meaning alinear, bivalent and saturated hydrocarbon group having 2 to 6,particularly 2, 3, 4 or 5 carbon atoms, as in “C₂-C₅-alkylene”, moreparticularly 2, 3 or 4 carbon atoms, as in “C₂-C₄-alkylene” e.g.ethylene, n-propylene, n-butylene, n-pentylene, or n-hexylene,preferably n-propylene or n-butylene.

The term “C₂-C₆-alkenyl-” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains onedouble bond, and which has 2, 3, 4, 5 or 6 carbon atoms(“C₂-C₆-alkenyl-”). Particularly, said alkenyl-group is aC₂-C₃-alkenyl-, C₃-C₆-alkenyl- or C₃-C₄-alkenyl-group. Saidalkenyl-group is, for example, a vinyl-, allyl-, (E)-2-methylvinyl-,(Z)-2-methylvinyl- or isopropenyl-group.

The term “C₂-C₆-alkynyl-” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group which contains onetriple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms.Particularly, said alkynyl-group is a C₂-C₃-alkynyl-, C₃-C₆-alkynyl- orC₃-C₄-alkynyl-group. Said C₂-C₃-alkynyl-group is, for example, anethynyl-, prop-1-ynyl- or prop-2-ynyl-group.

The term “C₃-C₇-cycloalkyl-” is to be understood as preferably meaning asaturated or partially unsaturated, monovalent, monocyclic hydrocarbonring which contains 3, 4, 5, 6 or 7 carbon atoms. SaidC₃-C₇-cycloalkyl-group is for example, a monocyclic hydrocarbon ring,e.g. a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl- orcycloheptyl-group. Said cycloalkyl-ring is non-aromatic but canoptionally contain one or more double bonds e.g. cycloalkenyl-, such asa cyclopropenyl-, cyclobutenyl-, cyclopentenyl-, cyclohexenyl- orcycloheptenyl-group, wherein the bond between said ring with the rest ofthe molecule may be to any carbon atom of said ring, be it saturated orunsaturated. Particularly, said cycloalkyl-group is a C₄-C₆-cycloalkyl-,a C₅-C₆-cycloalkyl- or a cyclohexyl-group.

The term “C₃-C₅-cycloalkyl-” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4or 5 carbon atoms. In particular said C₃-C₅-cycloalkyl-group is amonocyclic hydrocarbon ring such as a cyclopropyl-, cyclobutyl- orcyclopentyl-group. Preferably said “C₃-C₅-cycloalkyl-” group is acyclopropyl-group.

The term “C₃-C₄-cycloalkyl-” is to be understood as preferably meaning asaturated, monovalent, monocyclic hydrocarbon ring which contains 3 or 4carbon atoms. In particular, said C₃-C₄-cycloalkyl-group is a monocyclichydrocarbon ring such as a cyclopropyl- or cyclobutyl-group.

The term “heterocyclyl-” is to be understood as meaning a saturated orpartially unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and further containing1, 2 or 3 heteroatom-containing groups selected from oxygen, sulfur,nitrogen. Particularly, the term “heterocyclyl-” is to be understood asmeaning a “4- to 10-membered heterocyclic ring”.

The term “a 4- to 10-membered heterocyclic ring” is to be understood asmeaning a saturated or partially unsaturated, monovalent, mono- orbicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbonatoms, and further containing 1, 2 or 3 heteroatom-containing groupsselected from oxygen, sulfur, nitrogen.

A C₃-C₉-heterocyclyl- is to be understood as meaning aheterocyclyl-which contains at least 3, 4, 5, 6, 7, 8 or 9 carbon atomsand additionally at least one heteroatom as ring atoms. Accordingly incase of one heteroatom the ring is 4- to 10-membered, in case of twoheteroatoms the ring is 5- to 11-membered and in case of threeheteroatoms the ring is 6- to 12-membered.

Said heterocyclic ring is for example, a monocyclic heterocyclic ringsuch as an oxetanyl-, azetidinyl-, tetrahydrofuranyl-, pyrrolidinyl-,1,3-dioxolanyl-, imidazolidinyl-, pyrazolidinyl-, oxazolidinyl-,isoxazolidinyl-, 1,4-dioxanyl-, pyrrolinyl-, tetrahydropyranyl-,piperidinyl-, morpholinyl-, 1,3-dithianyl-, thiomorpholinyl-,piperazinyl-, or chinuclidinyl-group. Optionally, said heterocyclic ringcan contain one or more double bonds, e.g. 4H-pyranyl-, 2H-pyranyl-,2,5-dihydro-1H-pyrrolyl-, 1,3-dioxolyl-, 4H-1,3,4-thiadiazinyl-,2,5-dihydrofuranyl-, 2,3-dihydrofuranyl-, 2,5-dihydrothienyl-,2,3-dihydrothienyl-, 4,5-dihydrooxazolyl-, 4,5-dihydroisoxazolyl-, or4H-1,4-thiazinyl-group, or, it may be benzo fused.

Particularly, a C₃-C₇-heterocyclyl- is to be understood as meaning aheterocyclyl-which contains at least 3, 4, 5, 6, or 7 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 8-membered, in case of twoheteroatoms the ring is 5- to 9-membered and in case of threeheteroatoms the ring is 6- to 10-membered.

Particularly, a C₃-C₆-heterocyclyl- is to be understood as meaning aheterocyclyl-which contains at least 3, 4, 5 or 6 carbon atoms andadditionally at least one heteroatom as ring atoms. Accordingly in caseof one heteroatom the ring is 4- to 7-membered, in case of twoheteroatoms the ring is 5- to 8-membered and in case of threeheteroatoms the ring is 6- to 9-membered.

Particularly, the term “heterocyclyl-” is to be understood as being aheterocyclic ring which contains 3, 4 or 5 carbon atoms, and 1, 2 or 3of the above-mentioned heteroatom-containing groups (a “4- to 8-memberedheterocyclic ring”), more particularly said ring can contain 4 or 5carbon atoms, and 1, 2 or 3 of the above-mentioned heteroatom-containinggroups (a “5- to 8-membered heterocyclic ring”), more particularly saidheterocyclic ring is a “6-membered heterocyclic ring”, which is to beunderstood as containing 4 carbon atoms and 2 of the above-mentionedheteroatom-containing groups or 5 carbon atoms and one of theabove-mentioned heteroatom-containing groups, preferably 4 carbon atomsand 2 of the above-mentioned heteroatom-containing groups.

The term “C₁-C₆-alkoxy-” is to be understood as preferably meaning alinear or branched, saturated, monovalent, hydrocarbon group of formula—O-alkyl-, in which the term “alkyl-” is defined supra, e.g. a methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentyloxy, iso-pentyloxy, n-hexyloxy group, or an isomerthereof. Particularly, the “C₁-C₆-alkoxy-” group is a “C₁-C₄-alkoxy-”, a“C₁-C₃-alkoxy-”, a methoxy, ethoxy, or propoxy group, preferably amethoxy, ethoxy or propoxy group. Further preferred is a “C₁-C₂-alkoxy-”group, particularly a methoxy or ethoxy group.

The term “C₁-C₃-fluoroalkoxy-” is to be understood as preferably meaninga linear or branched, saturated, monovalent, C₁-C₃-alkoxy-group, asdefined supra, in which one or more of the hydrogen atoms is replaced,identically or differently, by one or more fluorine atoms. SaidC₁-C₃-fluoroalkoxy-group is, for example a 1,1-difluoromethoxy-, a1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-, a 3-fluoropropoxy-, a2,2,2-trifluoroethoxy-, a 3,3,3-trifluoropropoxy-, particularly a“C₁-C₂-fluoroalkoxy-” group.

The term “alkylamino-” is to be understood as preferably meaning analkylamino group with one linear or branched alkyl-group as definedsupra. (C₁-C₃)-alkylamino- for example means a monoalkylamino group with1, 2 oder 3 carbon atoms, (C₁-C₆)-alkylamino-with 1, 2, 3, 4, 5 or 6carbon atoms. The term “alkylamino-” comprises for example methylamino-,ethylamino-, n-propylamino-, iso-propylamino-, tert.-butylamino-,n-pentylamino- or n-hexylamino-.

The term “dialkylamino-” is to be understood as preferably meaning analkylamino group having two linear or branched alkyl-groups as definedsupra, which are independent from each other. (C₁-C₃)-dialkylamino—forexample represents a dialkylamino group with two alkyl groups each ofthem having 1 to 3 carbon atoms per alkyl group. The term“dialkylamino-” comprises for example: N,N-dimethylamino-,N,N-diethylamino-, N-ethyl-N-methylamino-, N-methyl-N-n-propylamino-,N-iso-propyl-N-n-propylamino-, N-tert-butyl-N-methylamino-,N-ethyl-N-n-pentylamino- and N-n-hexyl-N-methylamino-.

The term “cyclic amine” is to be understood as preferably meaning acyclic amine group. Preferably, a cyclic amine means a saturated,monocyclic group with 4 to 10, preferably 4 to 7 ring atoms of which atleast one ring atom is a nitrogen atom. Suitable cyclic amines areespecially azetidine, pyrrolidine, piperidine, piperazine,1-methylpiperazine, morpholine, thiomorpholine, which could beoptionally substituted by one or two methyl-groups.

The term “halo-C₁-C₃-alkyl-”, or, used synonymously, “C₁-C₃-haloalkyl-”,is to be understood as preferably meaning a linear or branched,saturated, monovalent hydrocarbon group in which the term “C₁-C₃-alkyl-”is defined supra, and in which one or more hydrogen atoms is replaced bya halogen atom, identically or differently, i.e. one halogen atom beingindependent from another. Preferably, a halo-C₁-C₃-alkyl-group is afluoro-C₁-C₃-alkyl- or a fluoro-C₁-C₂-alkyl-group, such as for example—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, or —CH₂CF₃, more preferably it is —CF₃.

The term “hydroxy-C₁-C₃-alkyl-”, is to be understood as preferablymeaning a linear or branched, saturated, monovalent hydrocarbon group inwhich the term “C₁-C₃-alkyl-” is defined supra, and in which one or morehydrogen atoms is replaced by hydroxy group, preferably not more thanone hydrogen atom per carbon atom being replaced by a hydroxy group.Particularly, a hydroxy-C₁-C₃-alkyl-group is, for example, —CH₂OH,—CH₂—CH₂OH, —C(H)OH—CH₂OH, —CH₂—CH₂—CH₂OH.

The term “phenyl-C₁-C₃-alkyl-” is to be understood as preferably meaninga phenyl-group, in which one of the hydrogen atoms is replaced by aC₁-C₃-alkyl-group, as defined supra, which links thephenyl-C₁-C₃-alkyl-group to the rest of the molecule. Particularly, the“phenyl-C₁-C₃-alkyl-” is a phenyl-C₁-C₂-alkyl-, preferably it is abenzyl-group.

The term “heteroaryl-” is to be understood as preferably meaning amonovalent, aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or14 ring atoms (a “5- to 14-membered heteroaryl-” group), particularly 5(a “5-membered heteroaryl-”) or 6 (a “6-membered heteroaryl-”) or 9 (a“9-membered heteroaryl-”) or 10 ring atoms (a “10-memberedheteroaryl-”), and which contains at least one heteroatom which may beidentical or different, said heteroatom being such as oxygen, nitrogenor sulfur, and can be monocyclic, bicyclic, or tricyclic, and inaddition in each case can be benzo-condensed. Particularly, heteroaryl-is selected from thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-,imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-,triazolyl-, thiadiazolyl-, tetrazolyl-etc., and benzo derivativesthereof, such as, for example, benzofuranyl-, benzothienyl-,benzoxazolyl-, benzisoxazolyl-, benzimidazolyl-, benzotriazolyl-,indazolyl-, indolyl-, isoindolyl-, etc.; or pyridyl-, pyridazinyl-,pyrimidinyl-, pyrazinyl-, triazinyl-, etc., and benzo derivativesthereof, such as, for example, quinolinyl-, quinazolinyl-,isoquinolinyl-, etc.; or azocinyl-, indolizinyl-, purinyl-, etc., andbenzo derivatives thereof; or cinnolinyl-, phthalazinyl-, quinazolinyl-,quinoxalinyl-, naphthyridinyl-, pteridinyl-, carbazolyl-, acridinyl-,phenazinyl-, phenothiazinyl-, phenoxazinyl-, xanthenyl-, or oxepinyl-,etc. Preferably, heteroaryl- is selected from monocyclic heteroaryl-,5-membered heteroaryl- or 6-membered heteroaryl-.

The term “5-membered heteroaryl-” is understood as preferably meaning amonovalent, aromatic ring system having 5 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“5-membered heteroaryl-” is selected from thienyl-, furanyl-, pyrrolyl-,oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-,isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-.

The term “6-membered heteroaryl-” is understood as preferably meaning amonovalent, aromatic ring system having 6 ring atoms and which containsat least one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur. Particularly,“6-membered heteroaryl-” is selected from pyridyl-, pyridazinyl-,pyrimidinyl-, pyrazinyl-, triazinyl-.

The term “heteroaryl-C₁-C₃-alkyl-” is to be understood as preferablymeaning a heteroaryl-, a 5-membered heteroaryl- or a 6-memberedheteroaryl-group, each as defined supra, in which one of the hydrogenatoms is replaced by a C₁-C₃-alkyl-group, as defined supra, which linksthe heteroaryl-C₁-C₃-alkyl-group to the rest of the molecule.Particularly, the “heteroaryl-C₁-C₃-alkyl-” is aheteroaryl-C₁-C₂-alkyl-, a pyridinyl-C₁-C₃-alkyl-, a pyridinylmethyl-, apyridinylethyl-, a pyridinylpropyl-, a pyrimidinyl-C₁-C₃-alkyl-, apyrimidinylmethyl-, a pyrimidinylethyl-, a pyrimidinylpropyl-,preferably a pyridinylmethyl- or a pyridinylethyl- or apyrimidinylethyl- or a pyrimidinylpropyl-group.

As used herein, the term “leaving group” refers to an atom or a group ofatoms that is displaced in a chemical reaction as stable species takingwith it the bonding electrons. Preferably, a leaving group is selectedfrom the group comprising: halo, in particular chloro, bromo or iodo,methanesulfonyloxy-, para-toluenesulfonyloxy-,trifluoromethanesulfonyloxy-, nonafluorobutanesulfonyloxy-,(4-bromo-benzene)sulfonyloxy-, (4-nitro-benzene)sulfonyloxy-,(2-nitro-benzene)-sulfonyloxy-, (4-isopropyl-benzene)sulfonyloxy-,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy-,(2,4,6-trimethyl-benzene)sulfonyloxy-,(4-tert-butyl-benzene)sulfonyloxy-, benzenesulfonyloxy-, and(4-methoxy-benzene)sulfonyloxy-.

As used herein, the term “C₁-C₃-alkylbenzene” refers to a partiallyaromatic hydrocarbon consisting of a benzene ring which is substitutedby one or two C₁-C₃-alkyl groups, as defined supra. Particularly,“C₁-C₃-alkylbenzene” is toluene, ethylbenzene, cumene, n-propylbenzene,ortho-xylene, meta-xylene or para-xylene. Preferably,“C₁-C₃-alkylbenzene” is toluene.

As used herein, the term “carboxamide based solvent” refers to loweraliphatic carboxamides of the formula C₁-C₂-alkyl-C(═O)—N(C₁-C₂-alkyl)₂,or lower cyclic aliphatic carboxamides of the formula

in which G represents —CH₂—, —CH₂—CH₂— or —CH₂—CH₂—CH₂—. Particularly,“carboxamide based solvent” is N,N-dimethylformamide,N,N-dimethylacetamide or N-methylpyrrolidin-2-one. Preferably,“carboxamide based solvent” is N,N-dimethylformamide orN-methyl-pyrrolidin-2-one.

The term “C₁-C₁₀”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₁₀-alkyl-” is to be understood as meaning analkyl-group having a finite number of carbon atoms of 1 to 10, i.e. 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is to be understoodfurther that said term “C₁-C₁₀” is to be interpreted as any sub-rangecomprised therein, e.g. C₁-C₁₀, C₁-C₉, C₁-C₈, C₁-C₇, C₁-C₆, C₁-C₅,C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₁₀, C₂-C₉, C₂-C₈, C₂-C₇, C₂-C₆, C₂-C₅, C₂-C₄,C₂-C₃, C₃-C₁₀, C₃-C₉, C₃-C₈, C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₁₀, C₄-C₉,C₄-C₈, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₁₀, C₅-C₉, C₅-C₈, C₅-C₇, C₅-C₆, C₆-C₁₀,C₆-C₉, C₆-C₈, C₆-C₇, C₇-C₁₀, C₇-C₉, C₇-C₈, C₈-C₁₀, C₈-C₉, C₉-C₁₀.

Similarly, as used herein, the term “C₁-C₆”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₆-alkyl-”,“C₁-C₆-alkoxy-” is to be understood as meaning an alkyl-group having afinite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbonatoms. It is to be understood further that said term “C₁-C₆” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₆, C₁-C₅,C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄,C₄-C₆, C₄-C₅, C₅-C₆.

Similarly, as used herein, the term “C₁-C₄”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₄-alkyl-”,“C₁-C₄-alkoxy-” is to be understood as meaning an alkyl-group having afinite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms.It is to be understood further that said term “C₁-C₄” is to beinterpreted as any sub-range comprised therein, e.g. C₁-C₄, C₁-C₃,C₁-C₂, C₂-C₄, C₂-C₃, C₃-C₄.

Similarly, as used herein, the term “C₁-C₃”, as used throughout thistext, e.g. in the context of the definition of “C₁-C₃-alkyl-”,“C₁-C₃-alkoxy-” or “C₁-C₃-fluoroalkoxy-” is to be understood as meaningan alkyl-group having a finite number of carbon atoms of 1 to 3, i.e. 1,2 or 3 carbon atoms. It is to be understood further that said term“C₁-C₃” is to be interpreted as any sub-range comprised therein, e.g.C₁-C₃, C₁-C₂, C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl-”, is to beunderstood as meaning a cycloalkyl-group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅,C₅-C₆. Further, as used herein, the term “C₃-C₇”, as used throughoutthis text, e.g. in the context of the definition of “C₃-C₇-cycloalkyl-”,is to be understood as meaning a cycloalkyl-group having a finite numberof carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms,particularly 3, 4, 5 or 6 carbon atoms. It is to be understood furtherthat said term “C₃-C₇” is to be interpreted as any sub-range comprisedtherein, e.g. C₃-C₇, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₇, C₄-C₆, C₄-C₅, C₅-C₇,C₅-C₆, C₆-C₇.

A symbol

at a bond denotes the linkage site in the molecule.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning one, two, three, four or five times,particularly one, two, three or four times, more particularly one, twoor three times, even more particularly one or two times.

Where the plural form of the word compounds, salts, hydrates, solvatesand the like, is used herein, this is taken to mean also a singlecompound, salt, isomer, hydrate, solvate or the like.

In another embodiment, the present invention concerns compounds ofgeneral formula (I), wherein

-   L represents a C₂-C₅-alkylene group,    -   wherein said group is optionally substituted with    -   (i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-,        hydroxy-C₁-C₃-alkyl-, —(CH₂)NR⁶R⁷, and/or    -   (ii) one or two or three additional substituents, identically or        differently, selected from a fluorine atom and a        C₁-C₃-alkyl-group,    -   with the proviso that a C₂-alkylene group is not substituted        with a hydroxy group,-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₆-alkyl- and    C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-,        fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂,        alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂,        —C(═O)OH, —C(═O)NH₂;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,    fluoro-C₁-C₂-alkyl-;-   R³, R⁴ represent, independently from each other, a group selected    from a hydrogen atom, a fluorine atom, a chlorine atom, cyano    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₆-alkyl-,    C₃-C₅-cycloalkyl-, phenyl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl- or phenyl-group is        optionally substituted with one, two or three substituents,        identically or differently, selected from the group consisting        of halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,        alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,        C₁-C₂-fluoroalkoxy-;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and    benzyl-,    -   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or        benzyl-group is optionally substituted with one, two or three        substituents, identically or differently, selected from the        group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines,        fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R⁸ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and benzyl-,    -   wherein said group is optionally substituted with one, two or        three substituents, identically or differently, selected from        the group consisting of halogen, hydroxy, C₁-C₃-alkyl-,        C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines,        fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-,-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₅-alkylene group,    -   wherein said group is optionally substituted with    -   (i) one substituent selected from C₃-C₄-cycloalkyl- and        hydroxymethyl-, and/or    -   (ii) one or two additional substituents, identically or        differently, selected from C₁-C₂-alkyl-,-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₄-alkyl- and    C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-,        C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,    trifluoromethoxy-;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,    C₃-C₅-cycloalkyl-, wherein said C₁-C₄-alkyl- or    C₃-C₅-cycloalkyl-group is optionally substituted with one    substituent selected from the group consisting of fluorine, hydroxy,    cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic    amines;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-,    -   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is        optionally substituted with one or two substituents, identically        or differently, selected from the group consisting of hydroxy,        C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        cyclic amines, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R⁸ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and phenyl-, wherein said    group is optionally substituted with one substituent selected from    the group consisting of halogen, hydroxy, C₁-C₂-alkyl-,    C₁-C₂-alkoxy-, —NH₂,-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₅-alkylene group,    -   wherein said group is optionally substituted with    -   (i) one substituent selected from C₃-C₄-cycloalkyl- and        hydroxymethyl-, and/or    -   (ii) one or two additional substituents, identically or        differently, selected from C₁-C₂-alkyl-,-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a group selected from C₁-C₄-alkyl- and    C₃-C₅-cycloalkyl-,    -   wherein said group is optionally substituted with one or two or        three substituents, identically or differently, selected from        the group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-,        C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,    trifluoromethoxy-;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one substituent selected from the group consisting of fluorine,        hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        cyclic amines;-   R⁶, R⁷ represent, independently from each other, a group selected    from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-,    -   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is        optionally substituted with one or two substituents, identically        or differently, selected from the group consisting of hydroxy,        C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,        cyclic amines, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine;-   R⁸ represents a group selected from C₁-C₆-alkyl-,    fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and phenyl-,    -   wherein said group is optionally substituted with one        substituent selected from the group consisting of halogen,        hydroxy, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, or the enantiomers,        diastereomers, salts, solvates or salts of solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a C₁-C₄-alkyl-group,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a group selected from a hydrogen atom and a fluorine    atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-, C₃—C-cycloalkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a C₁-C₄-alkyl-group,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a group selected from C₁-C₄-alkyl-,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a group selected from C₁-C₄-alkyl-,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a group selected from C₁-C₄-alkyl-,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a group selected from a hydrogen atom and a fluorine    atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₂-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a group selected from C₁-C₄-alkyl-,    -   wherein said group is optionally substituted with one or two        substituents, identically or differently, selected from the        group consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine atom    and a methoxy-group;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In a particularly preferred embodiment, the present invention concernscompounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁴ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-, cyclopropyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom or a fluorine atom;-   R⁴ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-, cyclopropyl,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a group selected from a hydrogen atom, a fluorine    atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₄-alkyl-,    -   wherein said C₁-C₄-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-, cyclopropyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom and a cyano group;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-, cyclopropyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a C₃-C₄-alkylene group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano,    C₁-C₃-alkyl-,    -   wherein said C₁-C₃-alkyl-group is optionally substituted with        one hydroxy group;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂— or a —CH₂CH₂CH₂CH₂CH₂CH₂— group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, cyano, methyl-,    3-hydroxypropyl- and cyclopropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.-   L represents a —CH₂CH₂CH₂— or a —CH₂CH₂CH₂CH₂— group;-   X, Y represent CH or N with the proviso that one of X and Y    represents CH and one of X and Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom, wherein R³ is attached in    para-position to the ring directly bonded to the phenyl-ring to    which R³ is attached which is a pyridine ring if Y represents CH and    a pyrimidine ring if Y represents N;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano, methyl-    and 3-hydroxypropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂— group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom or a cyano group;-   R³ represents a fluorine atom, wherein R³ is attached in    para-position to the ring directly bonded to the phenyl-ring to    which R³ is attached which is a pyridine ring if Y represents CH and    a pyrimidine ring if Y represents N;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano, methyl-    and 3-hydroxypropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂— group;-   X represents N;-   Y represents CH;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom, wherein R³ is attached in    para-position to the ring directly bonded to the phenyl-ring to    which R³ is attached which is a pyridine ring if Y represents CH and    a pyrimidine ring if Y represents N;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, cyano, methyl-    and 3-hydroxypropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂CH₂— group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from a hydrogen atom, methyl- and    cyclopropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂CH₂— group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom, wherein R³ is attached in    para-position to the ring directly bonded to the phenyl-ring to    which R³ is attached which is a pyridine ring if Y represents CH and    a pyrimidine ring if Y represents N;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from a hydrogen atom, methyl- and    cyclopropyl-;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another particularly preferred embodiment, the present inventionconcerns compounds of general formula (I), wherein

-   L represents a —CH₂CH₂CH₂CH₂— group;-   X represents CH;-   Y represents N;-   R¹ represents a methyl-group;-   R² represents a hydrogen atom;-   R³ represents a fluorine atom, wherein R³ is attached in    para-position to the ring directly bonded to the phenyl-ring to    which R³ is attached which is a pyridine ring if Y represents CH and    a pyrimidine ring if Y represents N;-   R⁴ represents a hydrogen atom;-   R⁵ represents a hydrogen atom;-   or the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

In another embodiment the invention relates to compounds of formula (I),in which L represents a C₂-C₅-alkylene group,

-   wherein said group is optionally substituted with-   (i) one substituent selected from hydroxy, —NR⁶R⁷, C₂-C₃-alkenyl-,    C₂-C₃-alkynyl-, C₃-C₄-cycloalkyl-, hydroxy-C₁-C₃-alkyl-,    —(CH₂)NR⁶R⁷, and/or-   (ii) one or two or three or four substituents, identically or    differently, selected from halogen and C₁-C₃-alkyl-,-   with the proviso that a C₂-alkylene group is not substituted with a    hydroxy or a —NR⁶R⁷ group, or wherein-   one carbon atom of said C₂-C₅-alkylene group forms a three- or    four-membered ring together with a bivalent group to which it is    attached, wherein said bivalent group is selected from —CH₂CH₂—,    —CH₂CH₂CH₂—, —CH₂OCH₂—.

In another embodiment the invention relates to compounds of formula (I),in which L represents a C₂-C₅-alkylene group,

-   wherein said group is optionally substituted with-   (i) one substituent selected from hydroxy, C₃-C₄-cycloalkyl-,    hydroxy-C₁-C₃-alkyl-, —(CH₂)NR⁶R⁷, and/or-   (ii) one or two or three additional substituents, identically or    differently, selected from a fluorine atom and a C₁-C₃-alkyl-group,-   with the proviso that a C₂-alkylene group is not substituted with a    hydroxy group.

In a preferred embodiment the invention relates to compounds of formula(I), in which L represents a C₂-C₅-alkylene group,

-   wherein said group is optionally substituted with-   (i) one substituent selected from C₃-C₄-cycloalkyl- and    hydroxymethyl-, and/or-   (ii) one or two additional substituents, identically or differently,    selected from C₁-C₂-alkyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which L represents a C₂-C₄-alkylene group, wherein saidgroup is optionally substituted with one or two methyl-groups.

In a another preferred embodiment the invention relates to compounds offormula (I), in which L represents a C₂-C₄-alkylene group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a C₃-C₄-alkylene group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a group —CH₂CH₂CH₂— or—CH₂CH₂CH₂CH₂—.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a group —CH₂CH₂CH₂—.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which L represents a group —CH₂CH₂CH₂CH₂—.

In another embodiment the invention relates to compounds of formula (I),in which X represents N, and in which Y represents CH.

In another embodiment the invention relates to compounds of formula (I),in which X represents CH, and in which Y represents N.

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₆-alkyl-,C₃-C₆-alkenyl-, C₃-C₆-alkynyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,phenyl-, heteroaryl-, phenyl-C₁-C₃-alkyl- and heteroaryl-C₁-C₃-alkyl-,

-   wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, halogen, C₁-C₆-alkyl-,    halo-C₁-C₃-alkyl-, C₁-C₆-alkoxy-, C₁-C₃-fluoroalkoxy-, —NH₂,    alkylamino-, dialkylamino-, acetylamino-, -methyl-N-acetylamino-,    cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, —C(═O)NH₂;

In another embodiment the invention relates to compounds of formula (I),in which R¹ represents a group selected from C₁-C₆-alkyl- andC₃-C₅-cycloalkyl-,

-   wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-,    fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH,    —C(═O)NH₂.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a group selected from C₁-C₄-alkyl- andC₃-C₅-cycloalkyl-,

-   wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, halogen, C₁-C₂-alkyl-,    C₁-C₂-alkoxy-, —NH₂, —C(═O)OH.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₄-alkyl-group,

-   wherein said group is optionally substituted with one or two or    three substituents, identically or differently, selected from the    group consisting of hydroxy, cyano, a fluorine atom, C₁-C₂-alkoxy-,    —NH₂, —C(═O)OH.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₄-alkyl-group,

-   wherein said group is optionally substituted with one or two    substituents, identically or differently, selected from the group    consisting of hydroxy, C₁-C₂-alkoxy-, —NH₂, —C(═O)OH.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₄-alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₃-alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₂-alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents an ethyl-group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl-group.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a C₁-C₄-alkyl-group, and R² represents ahydrogen atom or a fluorine atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R¹ represents a C₁-C₄-alkyl-group, and R² represents ahydrogen atom or a cyano group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a C₁-C₄-alkyl-group, and R²represents a hydrogen atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R¹ represents a methyl-group, and R² represents ahydrogen atom or a cyano group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl-group, and R²represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R² represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,fluoro-C₁-C₂-alkyl-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R² represents a group selected from a hydrogen atom, afluorine atom, a chlorine atom, cyano, methyl-, methoxy-,trifluoromethyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R² represents a hydrogen atom or a cyano group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R² represents a hydrogen atom or a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R² represents a cyano group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R² represents a fluorine atom.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R² represents a hydrogen atom, R³represents a fluorine atom, and R⁴ represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl-group, R²represents a hydrogen atom, R³ represents a fluorine atom, and R⁴represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R¹ represents a methyl-group, R²represents a hydrogen atom, and R³ represents a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent, independently from each other, a groupselected from a hydrogen atom, a fluorine atom, a chlorine atom, abromine atom, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-,C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent, independently from each other, a groupselected from a hydrogen atom, a fluorine atom, a chlorine atom, cyanoC₁-C₂-alkyl-, C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent, independently from each other, a groupselected from a hydrogen atom, a fluorine atom, a chlorine atom, cyano,methyl-, methoxy-, trifluoromethyl-, trifluoromethoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent, independently from each other, a hydrogenatom, a fluorine atom or a methoxy-group.

In another embodiment the invention relates to compounds of formula (I),in which R³ and R⁴ represent, independently from each other, a hydrogenatom or a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano, C₁-C₃-alkyl-,C₁-C₃-alkoxy-, halo-C₁-C₃-alkyl-, C₁-C₃-fluoroalkoxy-, and in which R⁴represents a hydrogen atom or a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano C₁-C₂-alkyl-,C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, and in which R⁴represents a hydrogen atom or a fluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, cyano C₁-C₂-alkyl-,C₁-C₂-alkoxy-, fluoro-C₁-C₂-alkyl-, C₁-C₂-fluoroalkoxy-, and in which R⁴represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy-, and in which R⁴ represents a hydrogen atom or afluorine atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy-, and in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluorine atom or amethoxy-group, and in which R⁴ represents a hydrogen atom or a fluorineatom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom, a fluorine atom or amethoxy-group, and in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a hydrogen atom or a fluorine atom, and in whichR⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a methoxy-group, and in which R⁴ represents ahydrogen atom.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a fluorine atom, and in which R⁴ representsa hydrogen atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a fluorine atom, and in which R⁴represents a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a fluorine atom, and in which R⁴represents a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group selected from

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group selected from

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group selected from

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group selected from

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another preferred embodiment the invention relates to compounds offormula (I), in which

represents a group selected from

in which * is the point of attachment to the pyridine ring (if Yrepresents CH) or the pyrimidine ring (if Y represents N) to which thephenyl ring shown is attached, and # is the point of attachment to themoiety —O-L-O—.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy-, and in which R⁴ represents a hydrogen atom,

-   wherein R³ is attached in para-position to the ring directly bonded    to the phenyl-ring to which R³ is attached which is a pyridine ring    if Y represents CH and a pyrimidine ring if Y represents N.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a hydrogen atom or a fluorine atom, and inwhich R⁴ represents a hydrogen atom,

-   wherein R³ is attached in para-position to the ring directly bonded    to the phenyl-ring to which R³ is attached which is a pyridine ring    if Y represents CH and a pyrimidine ring if Y represents N.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom, and inwhich R⁴ represents a hydrogen atom,

-   wherein R³ is attached in para-position to the ring directly bonded    to the phenyl-ring to which R³ is attached which is a pyridine ring    if Y represents CH and a pyrimidine ring if Y represents N.

In another embodiment the invention relates to compounds of formula (I),in which R³ represents a group selected from a hydrogen atom, a fluorineatom, a chlorine atom, cyano, methyl-, methoxy-, trifluoromethyl-,trifluoromethoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R³ represents a hydrogen atom or a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R³ represents a hydrogen atom.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R³ represents a fluorine atom,

-   wherein R³ is attached in para-position to the pyridine (if Y    represents CH) or pyrimidine (if Y represents N) ring directly    bonded to the phenyl-ring to which R³ is attached.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁴ represents a group selected from a hydrogen atom, afluorine atom, a chlorine atom, cyano, methyl-, methoxy-,trifluoromethyl-, trifluoromethoxy-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁴ represents a hydrogen atom or a fluorine atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁴ represents a fluorine atom.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁴ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a group selected from a hydrogen atom, cyano,—C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₆-alkyl-,C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, heteroaryl-,

-   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-    or heteroaryl-group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-,    —NH₂, alkylamino-, dialkylamino-, acetylamino-,    N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,    C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁵ represents a group selected from a hydrogen atom, cyano,—C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₆-alkyl-,C₃-C₅-cycloalkyl-, phenyl-,

-   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl- or phenyl-group is    optionally substituted with one, two or three substituents,    identically or differently, selected from the group consisting of    halogen, hydroxy, cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a group selected from a hydrogen atom,cyano, —C(═O)R⁸, —C(═O)OR, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionally    substituted with one substituent selected from the group consisting    of fluorine, hydroxy, cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-,    dialkylamino-, cyclic amines.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁵ represents a group selected from a hydrogen atom,cyano, —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    substituent selected from the group consisting of fluorine, hydroxy,    cyano, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic    amines.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)OR, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, —C(═O)OR⁸, —C(═O)NR⁶R⁷, C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, C₁-C₄-alkyl-, C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁵ represents a group selected from a hydrogenatom, cyano, C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    hydroxy group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a group selected from ahydrogen atom, cyano, C₁-C₃-alkyl-, cyclopropyl-,

-   wherein said C₁-C₃-alkyl-group is optionally substituted with one    hydroxy group.

In a particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a group selected from ahydrogen atom, cyano, C₁-C₃-alkyl-,

-   wherein said C₁-C₃-alkyl-group is optionally substituted with one    hydroxy group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a group selected from ahydrogen atom, cyano, methyl-, 3-hydroxypropyl- and cyclopropyl.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a group selected from ahydrogen atom, cyano, methyl- and 3-hydroxypropyl-.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a hydrogen atom.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a cyano group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents methyl-group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a3-hydroxypropyl-group.

In another particularly preferred embodiment the invention relates tocompounds of formula (I), in which R⁵ represents a cyclopropyl-group.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ and R⁷ represent, independently from each other, a groupselected from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-,heterocyclyl-, phenyl-, benzyl- and heteroaryl-,

-   wherein said C₁-C₆-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-,    phenyl-, benzyl- or heteroaryl-group is optionally substituted with    one, two or three substituents, identically or differently, selected    from the group consisting of halogen, hydroxy, C₁-C₃-alkyl-,    C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, acetylamino-,    N-methyl-N-acetylamino-, cyclic amines, halo-C₁-C₃-alkyl-,    C₁-C₃-fluoroalkoxy-, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ and R⁷ represent, independently from each other, a groupselected from a hydrogen atom, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl-and benzyl-,

-   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or    benzyl-group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom,C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and benzyl-,

-   wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or    benzyl-group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-, and in which R⁷ represents a hydrogen atom or a    C₁-C₃ alkyl-group, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom,C₁-C₆-alkyl- and phenyl-,

-   wherein said C₁-C₆-alkyl- or phenyl-group is optionally substituted    with one, two or three substituents, identically or differently,    selected from the group consisting of halogen, hydroxy,    C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-, and in which R⁷    represents a hydrogen atom or a C₁-C₃ alkyl-group, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a group selected from a hydrogen atom,C₁-C₆-alkyl- and phenyl-,

-   wherein said C₁-C₆-alkyl- or phenyl-group is optionally substituted    with one, two or three substituents, identically or differently,    selected from the group consisting of halogen, hydroxy,    C₁-C₃-alkyl-, C₁-C₃-alkoxy-, dialkylamino-, and in which R⁷    represents a hydrogen atom or a C₁-C₃ alkyl-group.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ and R⁷, together with the nitrogen atom they are attachedto, form a cyclic amine.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁶ and R⁷ represent, independently from each other, agroup selected from a hydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionally    substituted with one or two substituents, identically or    differently, selected from the group consisting of hydroxy,    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,    cyclic amines, or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a group selected from a hydrogenatom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionally    substituted with one or two substituents, identically or    differently, selected from the group consisting of hydroxy,    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,    cyclic amines,-   and in which R⁷ represents a hydrogen atom or a C₁-C₃ alkyl-group,    or-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a group selected from a hydrogenatom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-,

-   wherein said C₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionally    substituted with one or two substituents, identically or    differently, selected from the group consisting of hydroxy,    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-,    cyclic amines,-   and in which R⁷ represents a hydrogen atom or a C₁-C₃ alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷ represent, independently from eachother, a group selected from a hydrogen atom and C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    substituent selected from the group consisting of hydroxy,    C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a group selected from a hydrogenatom and C₁-C₄-alkyl-,

-   wherein said C₁-C₄-alkyl-group is optionally substituted with one    substituent selected from the group consisting of hydroxy,    C₁-C₂-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclic amines, and    in which R⁷ represents a hydrogen atom or a C₁-C₃ alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷ represent, independently from eachother, a group selected from a hydrogen atom, C₁-C₄-alkyl- andC₃-C₅-cycloalkyl-, or

-   R⁶ and R⁷, together with the nitrogen atom they are attached to,    form a cyclic amine.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷ represent, independently from eachother, a group selected from a hydrogen atom, C₁-C₄-alkyl- andC₃-C₅-cycloalkyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ and R⁷ represent, independently from eachother, a group selected from a hydrogen atom, a methyl- and anethyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a group selected from a hydrogenatom, a methyl- and an ethyl-group, and in which R⁷ represents ahydrogen atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a group selected from a hydrogenatom, a methyl- and an ethyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁷ represents a hydrogen atom.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁶ represents a methyl- or an ethyl-group, and inwhich R⁷ represents a hydrogen atom.

In another embodiment the invention relates to compounds of formula (I),in which R⁶ represents a methyl- or an ethyl-group.

In another embodiment the invention relates to compounds of formula (I),in which R⁸ represents a group selected from C₁-C₆-alkyl-,halo-C₁-C₃-alkyl-, C₃-C₇-cycloalkyl-, heterocyclyl-, phenyl-, benzyl-and heteroaryl-,

-   wherein said group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,    alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,    cyclic amines, halo-C₃-C₃-alkyl-, C₁-C₃-fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I),in which R⁸ represents a group selected from C₁-C₆-alkyl-,fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-, phenyl- and benzyl-,

-   wherein said group is optionally substituted with one, two or three    substituents, identically or differently, selected from the group    consisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,    alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-,    C₁-C₂-fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula(I), in which R⁸ represents a group selected from C₁-C₆-alkyl-,fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and phenyl-,

-   wherein said group is optionally substituted with one substituent    selected from the group consisting of halogen, hydroxy,    C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a group selected from C₁-C₃-alkyl-,fluoro-C₁-C₂-alkyl- and phenyl-,

-   wherein said group is optionally substituted with one substituent    selected from the group consisting of fluorine, hydroxy, methyl-,    methoxy-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a group selected from C₁-C₃-alkyl-,fluoro-C₁-C₂-alkyl- and phenyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a group selected from C₁-C₄-alkyl-,fluoro-C₁-C₃-alkyl-.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a C₁-C₄-alkyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a methyl- or an ethyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents a methyl-group.

In another preferred embodiment the invention relates to compounds offormula (I), in which R⁸ represents an ethyl-group.

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of formula (I), supra.

More particularly still, the present invention covers compounds offormula (I) which are disclosed in the Example section of this text,infra.

Very specially preferred are combinations of two or more of theabovementioned preferred embodiments.

In particular, a preferred subject of the present invention is acompound selected from:

-   15,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine;-   (rac)-3-(2-{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}-2-methyl-2λ⁶-diazathia-1,2-dien-1-yl)propan-1-ol;-   (rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(imino)methyl-λ⁶-sulfanylidene]cyanamide;-   (rac)-8-[(N,S-dimethylsulfonodiimidoyl)methyl]-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine,    and-   16,20-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;-   16,20,21-trifluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;-   16,21-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;-   15,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7-carbonitrile;-   (rac)-9-[(N-cyclopropyl-S-methylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;-   (rac)-9-[(N,S-dimethylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;-   and the enantiomers, diastereomers, salts, solvates or salts of    solvates thereof.

The above mentioned definitions of groups and radicals which have beendetailed in general terms or in preferred ranges also apply to the endproducts of the formula (I) and, analogously, to the starting materialsor intermediates required in each case for the preparation.

The present invention further relates to a process for the preparationof the compounds of formula (10), in which R¹, R², R³, R⁴, R⁵ and L areas defined for the compounds of formula (I) according to the invention,

-   in which process compounds of formula (9)

-   in which R¹, R², R³, R⁴ and L are as defined for the compound of    formula (I) according to the invention, are oxidised by treatment    with an agent selected from iodobenzene diacetate and N-chloro    succinimide, followed by the addition of an amine selected from a    primary amine of the formula R⁵—NH₂, in which R⁵ is as defined for    the compounds of formula (I) according to the invention, and    hexamethyldisilazene, to give compounds of the formula (10),

and in which process the resulting compounds are optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

The present invention further relates to a process for the preparationof the compounds of formula (23), in which R¹, R², R³, R⁴, R⁵ and L areas defined for the compounds of formula (I) according to the invention,

in which process compounds of formula (22)

in which R¹, R², R³, R⁴ and L are as defined for the compound of formula(I) according to the invention, are oxidised by treatment with an agentselected from iodobenzene diacetate and N-chloro succinimide, followedby the addition of an amine selected from a primary amine of the formulaR⁵—NH₂, in which R⁵ is as defined for the compounds of formula (I)according to the invention, and hexamethyldisilazene, to give compoundsof the formula (23),

and in which process the resulting compounds are optionally, ifappropriate, converted with the corresponding (i) solvents and/or (ii)bases or acids to the solvates, salts and/or solvates of the saltsthereof.

The invention further relates to compounds of the formula (9), in whichR¹, R², R³, R⁴ and L are as defined for the compound of formula (I)according to the invention,

or the enantiomers, diastereomers or solvates thereof.

The invention further relates to the use of the compounds of the formula(9), in which R¹, R², R³, R⁴ and L are as defined for the compound offormula (I) according to the invention,

or the enantiomers, diastereomers or solvates thereof, for thepreparation of compounds of the formula (I).

The invention further relates to compounds of the formula (22), in whichR¹, R², R³, R⁴ and L are as defined for the compound of formula (I)according to the invention,

or the enantiomers, diastereomers or solvates thereof.

The invention further relates to the use of the compounds of the formula(22), in which R¹, R², R³, R⁴ and L are as defined for the compound offormula (I) according to the invention,

or the enantiomers, diastereomers or solvates thereof, for thepreparation of compounds of the formula (I).

The compounds according to the invention show a valuable pharmacologicaland pharmacokinetic spectrum of action which could not have beenpredicted.

They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of disorders in humans and animals.

The pharmaceutical activity of the compounds according to the inventioncan be explained by their action as selective inhibitors of CDK9, and,more significantly, as selective inhibitors of CDK9 at high ATPconcentrations.

Thus, the compounds according to the general formula (I) as well as theenantiomers, diastereomers, salts, solvates and salts of solvatesthereof are used as selective inhibitors for CDK9.

Furthermore, the compounds according to the invention show aparticularly high potency (demonstrated by a low IC₅₀ value in theCDK9/CycT1 assay) for selectively inhibiting CDK9 activity, inparticular at high ATP concentrations.

In context of the present invention, the IC₅₀ value with respect to CDK9can be determined by the methods described in the method section below.

As compared to many CDK9 inhibitors described in the prior art,compounds of the present invention according to general formula (I) showa surprisingly high potency for inhibiting CDK9 activity, especially athigh ATP concentrations, which is demonstrated by their low IC₅₀ valuein the CDK9/CycT1 high ATP kinase assay. Thus, these compounds have alower probability to be competed out of the ATP-binding pocket ofCDK9/CycT1 kinase due to the high intracellular ATP concentration (R.Copeland et al., Nature Reviews Drug Discovery 2006, 5, 730-739).According to this property the compounds of the present invention areparticularly able to inhibit CDK9/CycT1 within cells for a longer periodof time as compared to classical ATP competitive kinase inhibitors. Thisincreases the anti-tumor cell efficacy at pharmacokineticclearance-mediated declining serum concentrations of the inhibitor afterdosing of a patient or an animal.

As compared to CDK9 inhibitors in the prior art, compounds in thepresent invention show a surprisingly long target residence time. It hasbeen suggested earlier that the target residence time is an appropriatepredictor for drug efficacy on the basis that equilibrium-based in vitroassays inadequately reflect in vivo situations where drug concentrationsfluctuate due to adsorption, distribution and elimination processes andthe target protein concentration may be dynamically regulated (Tummino,P. J. and R. A. Copeland, Residence time of receptor-ligand complexesand its effect on biological function. Biochemistry, 2008. 47 (20): p.5481-5492; Copeland, R. A., D. L. Pompliano, and T. D. Meek, Drug-targetresidence time and its implications for lead optimization. NatureReviews Drug Discovery, 2006. 5 (9): p. 730-739).

Therefore, the equilibrium binding parameter, K_(D), or the functionalrepresentative, IC₅₀, may not fully reflect requirements for in vivoefficacy. Assuming that a drug molecule can only act as long as itremains bound to its target, the “lifetime” (residence time), of thedrug-target complex may serve as a more reliable predictor for drugefficacy in a non-equilibrium in vivo system. Several publicationsappreciated and discussed its implications for in vivo efficacy (Lu, H.and P. J. Tonge, Drug-target residence time: critical information forlead optimization. Curr Opin Chem Biol, 2010. 14 (4): p. 467-74;Vauquelin, G. and S. J. Charlton, Long-lasting target binding andrebinding as mechanisms to prolong in vivo drug action. Br J Pharmacol,2010. 161 (3): p. 488-508).

One example for the impact of target residence time is given by the drugtiotropium that is used in COPD treatment. Tiotropium binds to the M1,M2 and M3 subtype of the muscarinic receptors with comparableaffinities, but is kinetically selective as it has the desired longresidence times only for the M3 receptor. Its drug-target residence timeis sufficiently long that after washout from human trachea in vitro,tiotropium maintains inhibition of cholinergic activity with a half-lifeof 9 hours. This translates to protection against bronchospasms for morethan 6 hours in vivo (Price, D., A. Sharma, and F. Cerasoli, Biochemicalproperties, pharmacokinetics and pharmacological response of tiotropiumin chronic obstructive pulmonary disease patients. 2009; Dowling, M.(2006) Br. J. Pharmacol. 148, 927-937).

Another example is Lapatinib (Tykerb). It was found was that the longtarget residence time found for lapatinib in the purified intracellulardomain enzyme reaction correlated with the observed, prolonged signalinhibition in tumor cells based on receptor tyrosine phosphorylationmeasurements. It was subsequently concluded that the slow bindingkinetics may offer increased signal inhibition in the tumor, thusleading to greater potential to affect the tumor growth rates oreffectiveness of co-dosing with other chemotherapeutic agents. (Wood etal (2004) Cancer Res. 64: 6652-6659; Lackey (2006) Current Topics inMedicinal Chemistry, 2006, Vol. 6, No. 5)

In context of the present invention, the IC₅₀ value with respect to CDK9at high ATP concentrations can be determined by the methods described inthe method section below. Preferably, it is determined according toMethod 1b (“CDK9/CycT1 high ATP kinase assay”) as described in theMaterials and Method section below.

If desired, the IC₅₀ value with respect to CDK9 at low ATP concentrationcan e.g. be determined by the methods described in the method sectionbelow, according to Method 1a. (“CDK9/CycT1 kinase assay”) described inthe Materials and Method section below.

In context of the present invention, the target resident time ofselective CDK9 inhibitors according to the present invention can bedetermined by the methods described in the method section below.Preferably, it is determined according to Method 8 (“Surface PlasmonResonance PTEFb”) as described in the Materials and Method sectionbelow.

Further, compounds of the present invention according to formula (I)surprisingly show an exceptionally high anti-proliferative activity intumor cell lines, such as HeLa, HeLa-MaTu-ADR, NCI—H460, DU145, Caco-2,B16F10, A2780 or MOLM-13, compared to CDK9 inhibitors described in theprior art.

In context of the present invention, the anti-proliferative activity intumor cell lines such as HeLa, HeLa-MaTu-ADR, NCI—H460, DU145, Caco-2,B16F10, A2780 or MOLM-13 is preferably determined according to Method 3.(“Proliferation Assay”) as described in the Materials and Method sectionbelow.

In context of the present invention, the metabolic stability in rathepatocytes is preferably determined according to Method 6.(“Investigation of in vitro metabolic stability in rat hepatocytes”)described in the Materials and Method section below.

In context of the present invention, the half-life in rats uponadministration in vivo is preferably determined according to Method 7.(“In vivo pharmacokinetics in rats”) described in the Materials andMethod section below.

Further, compounds of the present invention according to formula (I) arecharacterized by an acceptable Caco-2 permeability (P_(app) A−B) acrossCaco-2 cell monolayers.

Further, compounds of the present invention according to formula (I) arecharacterized by an acceptable efflux ratio (efflux ratio=P_(app)B−A/P_(app) A−B) from the basal to apical compartment across Caco-2 cellmonolayers, compared to compounds known from the prior art.

In context of the present invention, the apparent Caco-2 permeabilityvalues from the basal to apical compartment (P_(app) A−B) or the effluxratio (defined as the ratio ((P_(app) B−A)/(P_(app) A−B)) are preferablydetermined according to Method 5. (“Caco-2 Permeation Assay”) describedin the Materials and Method section below.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, preferably of disordersrelating to or mediated by CDK9 activity, in particular ofhyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases, more preferably ofhyper-proliferative disorders.

The compounds of the present invention may be used to inhibitselectively the activity or expression of CDK9.

Therefore, the compounds of formula (I) are expected to be valuable astherapeutic agents. Accordingly, in another embodiment, the presentinvention provides a method of treating disorders relating to ormediated by CDK9 activity in a patient in need of such treatment,comprising administering to the patient an effective amount of acompound of formula (I) as defined above. In certain embodiments, thedisorders relating to CDK9 activity are hyper-proliferative disorders,virally induced infectious diseases and/or of cardiovascular diseases,more preferably hyper-proliferative disorders, particularly cancer.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable ofsuffering from a cell proliferative disorder or a disorder associatedwith reduced or insufficient programmed cell death (apoptosis) or whocould otherwise benefit from the administration of a compound of theinvention, such as human and non-human animals. Preferred humans includehuman patients suffering from or prone to suffering from a cellproliferative disorder or associated state, as described herein. Theterm “non-human animals” includes vertebrates, e.g., mammals, such asnon-human primates, sheep, cow, dog, cat and rodents, e.g., mice, andnon-mammals, such as chickens, amphibians, reptiles, etc.

The term “disorders relating to or mediated by CDK9” shall includediseases associated with or implicating CDK9 activity, for example thehyperactivity of CDK9, and conditions that accompany with thesediseases. Examples of “disorders relating to or mediated by CDK9”include disorders resulting from increased CDK9 activity due tomutations in genes regulating CDK9 activity such as LARP7, HEXIM1/2 or7sk snRNA, or disorders resulting from increased CDK9 activity due toactivation of the CDK9/cyclinT/RNApolymerase II complex by viralproteins such as HIV-TAT or HTLV-TAX or disorders resulting fromincreased CDK9 activity due to activation of mitogenic signalingpathways. The term “hyperactivity of CDK9” refers to increased enzymaticactivity of CDK9 as compared to normal non-diseased cells, or it refersto increased CDK9 activity leading to unwanted cell proliferation, or toreduced or insufficient programmed cell death (apoptosis), or mutationsleading to constitutive activation of CDK9.

The term “hyper-proliferative disorder” includes disorders involving theundesired or uncontrolled proliferation of a cell and it includesdisorders involving reduced or insufficient programmed cell death(apoptosis). The compounds of the present invention can be utilized toprevent, inhibit, block, reduce, decrease, control, etc., cellproliferation and/or cell division, and/or produce apoptosis. Thismethod comprises administering to a subject in need thereof, including amammal, including a human, an amount of a compound of this invention, ora pharmaceutically acceptable salt, hydrate or solvate thereof which iseffective to treat or prevent the disorder.

Hyper-proliferative disorders in the context of this invention include,but are not limited to, e.g., psoriasis, keloids and other hyperplasiasaffecting the skin, endometriosis, skeletal disorders, angiogenic orblood vessel proliferative disorders, pulmonary hypertension, fibroticdisorders, mesangial cell proliferative disorders, colonic polyps,polycystic kidney disease, benign prostate hyperplasia (BPH), and solidtumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid, and their distant metastases. Thosedisorders also include lymphomas, sarcomas and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ, and canine or feline mammary carcinoma.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma, pleuropulmonary blastoma, and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodennal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginaland vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, salivary gland cancers, anal gland adenocarcinomas, andmast cell tumors.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral, and hereditary andsporadic papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer,non-melanoma skin cancer, and mast cell tumors.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer, squamous cell cancer, and oral melanoma.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma,rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma,hemangiosarcoma, hemangiopericytoma, and leiomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

Fibrotic proliferative disorders, i.e. the abnormal formation ofextracellular matrices, that may be treated with the compounds andmethods of the present invention include lung fibrosis, atherosclerosis,restenosis, hepatic cirrhosis, and mesangial cell proliferativedisorders, including renal diseases such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyn-dromes, transplant rejection, and glomerulopathies.

Other conditions in humans or other mammals that may be treated byadministering a compound of the present invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age-related maculardegeneration, rheumatoid arthritis, psoriasis, and bullous disordersassociated with subepidermal blister formation, including bullouspemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention may also be used to prevent andtreat diseases of the airways and the lung, diseases of thegastrointestinal tract as well as diseases of the bladder and bile duct.

The disorders mentioned above have been well characterized in humans,but also exist with a similar etiology in other animals, includingmammals, and can be treated by administering pharmaceutical compositionsof the present invention.

In a further aspect of the present invention, the compounds according tothe invention are used in a method for preventing and/or treatinginfectious diseases, in particular virally induced infectious diseases.The virally induced infectious diseases, including opportunisticdiseases, are caused by retroviruses, hepadnaviruses, herpesviruses,flaviviridae, and/or adenoviruses. In a further preferred embodiment ofthis method, the retroviruses are selected from lentiviruses oroncoretroviruses, wherein the lentivirus is selected from the groupcomprising: HIV-1, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV,preferably HIV-1 or HIV-2 and wherein the oncoretrovirus is selectedfrom the group of: HTLV-I, HTLV-II or BLV. In a further preferredembodiment of this method, the hepadnavirus is selected from HBV, GSHVor WHV, preferably HBV, the herpesivirus is selected from the groupcomprising: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV andthe flaviviridae is selected from HCV, West nile or Yellow Fever.

The compounds according to general formula (I) are also useful forprophylaxis and/or treatment of cardiovascular diseases such as cardiachypertrophy, adult congenital heart disease, aneurysm, stable angina,unstable angina, angina pectoris, angioneurotic edema, aortic valvestenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventriculardysplasia, arteriosclerosis, arteriovenous malformations, atrialfibrillation, Behcet syndrome, bradycardia, cardiac tamponade,cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy,restrictive cardiomyopathy, cardiovascular disease prevention, carotidstenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes,Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism, bacterialendocarditis, fibromuscular dysplasia, congenital heart defects, heartdiseases, congestive heart failure, heart valve diseases, heart attack,epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia,hypertension, pulmonary hypertension, hypertrophic growth, leftventricular hypertrophy, right ventricular hypertrophy, hypoplastic leftheart syndrome, hypotension, intermittent claudication, ischemic heartdisease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome,long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneouslymph node syndrome, myocardial infarction, myocardial ischemia,myocarditis, pericarditis, peripheral vascular diseases, phlebitis,polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis,Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X,tachycardia, Takayasu's arteritis, hereditary hemorrhagictelangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot,thromboangiitis obliterans, thrombosis, thromboembolism, tricuspidatresia, varicose veins, vascular diseases, vasculitis, vasospasm,ventricular fibrillation, Williams syndrome, peripheral vasculardisease, varicose veins and leg ulcers, deep vein thrombosis,Wolff-Parkinson-White syndrome.

Preferred are cardiac hypertrophy, adult congenital heart disease,aneurysms, angina, angina pectoris, arrhythmias, cardiovascular diseaseprevention, cardiomyopathies, congestive heart failure, myocardialinfarction, pulmonary hypertension, hypertrophic growth, restenosis,stenosis, thrombosis and arteriosclerosis.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention as amedicament.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of disorders, in particular of thedisorders mentioned above.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of hyper-proliferative disorders, virallyinduced infectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention for thetreatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use as amedicament.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of the disorders mentioned above.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of hyper-proliferative disorders, virally inducedinfectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use of treatingand/or prophylaxis of lung carcinomas, especially non-small cell lungcarcinomas, prostate carcinomas, especially hormone-independent humanprostate carcinomas, cervical carcinomas, including multidrug-resistanthuman cervical carcinomas, colorectal carcinomas, melanomas, ovariancarcinomas or leukemias, especially acute myeloid leukemias.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodfor the treatment and/or prophylaxis of the disorders mentioned above.

A further subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodfor the treatment and/or prophylaxis of hyper-proliferative disorders,virally induced infectious diseases and/or of cardiovascular diseases.

A preferred subject matter of the present invention are the compounds ofgeneral formula (I) according to the invention for the use in a methodof treatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

A further subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis ofhyper-proliferative disorders, virally induced infectious diseasesand/or of cardiovascular diseases.

A preferred subject matter of the present invention is the use of thecompounds of general formula (I) according to the invention in themanufacture of a medicament for the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

A further subject matter of the present invention is a method for thetreatment and/or prophylaxis of disorders, in particular the disordersmentioned above, using an effective amount of the compounds of generalformula (I) according to the invention.

A further subject matter of the present invention is a method for thetreatment and/or prophylaxis of hyper-proliferative disorders, virallyinduced infectious diseases and/or of cardiovascular diseases, using aneffective amount of the compounds of general formula (I) according tothe invention.

A preferred subject matter of the present invention is a method for thetreatment and/or prophylaxis of lung carcinomas, especially non-smallcell lung carcinomas, prostate carcinomas, especiallyhormone-independent human prostate carcinomas, cervical carcinomas,including multidrug-resistant human cervical carcinomas, colorectalcarcinomas, melanomas, ovarian carcinomas or leukemias, especially acutemyeloid leukemias using an effective amount of the compounds of generalformula (I) according to the invention.

Another aspect of the present invention relates to pharmaceuticalcombinations comprising a compound of general formula (I) according tothe invention in combination with at least one or more further activeingredients.

As used herein the term “pharmaceutical combination” refers to acombination of at least one compound of general formula (I) according tothe invention as active ingredient together with at least one otheractive ingredient with or without further ingredients, carrier, diluentsand/or solvents.

Another aspect of the present invention relates to pharmaceuticalcompositions comprising a compound of general formula (I) according tothe invention in combination with an inert, nontoxic, pharmaceuticallysuitable adjuvant.

As used herein the term “pharmaceutical composition” refers to a galenicformulation of at least one pharmaceutically active agent together withat least one further ingredient, carrier, diluent and/or solvent.

Another aspect of the present invention relates to the use of thepharmaceutical combinations and/or the pharmaceutical compositionsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular of the disorders mentioned above.

Another aspect of the present invention relates to the use of thepharmaceutical combinations and/or the pharmaceutical compositionsaccording to the invention for the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

Another aspect of the present invention relates to pharmaceuticalcombinations and/or the pharmaceutical compositions according to theinvention for use of the treatment and/or prophylaxis of disorders, inparticular of the disorders mentioned above.

Another aspect of the present invention relates to pharmaceuticalcombinations and/or the pharmaceutical compositions according to theinvention for use of the treatment and/or prophylaxis of lungcarcinomas, especially non-small cell lung carcinomas, prostatecarcinomas, especially hormone-independent human prostate carcinomas,cervical carcinomas, including multidrug-resistant human cervicalcarcinomas, colorectal carcinomas, melanomas, ovarian carcinomas orleukemias, especially acute myeloid leukemias.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thispharmaceutical combination includes administration of a singlepharmaceutical dosage formulation which contains a compound of formula(I) and one or more additional therapeutic agents, as well asadministration of the compound of formula (I) and each additionaltherapeutic agent in its own separate pharmaceutical dosage formulation.For example, a compound of formula (I) and a therapeutic agent may beadministered to the patient together in a single oral dosage compositionsuch as a tablet or capsule, or each agent may be administered inseparate dosage formulations.

Where separate dosage formulations are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate combination with other anti-tumor agents such asalkylating agents, anti-metabolites, plant-derived anti-tumor agents,hormonal therapy agents, topoisomerase inhibitors, camptothecinderivatives, kinase inhibitors, targeted drugs, antibodies, interferonsand/or biological response modifiers, anti-angiogenic compounds, andother anti-tumor drugs. In this regard, the following is a non-limitinglist of examples of secondary agents that may be used in combinationwith the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, bendamustin, and        mitolactol; platinum-coordinated alkylating compounds include,        but are not limited to, cisplatin, carboplatin, eptaplatin,        lobaplatin, nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as finasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-n1, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge; Merial melanoma vaccine    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofiran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, recentin, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, DAST, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, removab, revlimid,        sorafenib, vatalanib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab,        sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib        alaninate, vatalanib, pazopanib, and ranibizumab; Palladia    -   EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors        (such as e.g. RDEA 119) and Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifarnib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib,        AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate,        brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;        Palladia, masitinib    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydrochloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, amino-glutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

-   (1) yield better efficacy in reducing the growth of a tumor or even    eliminate the tumor as compared to administration of either agent    alone,-   (2) provide for the administration of lesser amounts of the    administered chemotherapeutic agents,-   (3) provide for a chemotherapeutic treatment that is well tolerated    in the patient with fewer deleterious pharmacological complications    than observed with single agent chemotherapies and certain other    combined therapies,-   (4) provide for treating a broader spectrum of different cancer    types in mammals, especially humans,-   (5) provide for a higher response rate among treated patients,-   (6) provide for a longer survival time among treated patients    compared to standard chemotherapy treatments,-   (7) provide a longer time for tumor progression, and/or-   (8) yield efficacy and tolerability results at least as good as    those of the agents used alone, compared to known instances where    other cancer agent combinations produce antagonistic effects.

Furthermore, the compounds of formula (I) may be utilized, as such or incompositions, in research and diagnostics, or as analytical referencestandards, and the like, which are well known in the art.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitable way,such as, for example, by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route, or as an implant or stent.

For these administration routes, it is possible to administer thecompounds according to the invention in suitable application forms.

Suitable for oral administration are administration forms which work asdescribed in the prior art and deliver the compounds according to theinvention rapidly and/or in modified form, which comprise the compoundsaccording to the invention in crystalline and/or amorphous and/ordissolved form, such as, for example, tablets (coated or uncoated, forexample tablets provided with enteric coatings or coatings whosedissolution is delayed or which are insoluble and which control therelease of the compound according to the invention), tablets whichrapidly decompose in the oral cavity, or films/wafers,films/lyophilizates, capsules (for example hard or soft gelatincapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (for example intravenously, intraarterially, intracardially,intraspinally or intralumbally) or with inclusion of absorption (forexample intramuscularly, subcutaneously, intracutaneously,percutaneously or intraperitoneally). Administration forms suitable forparenteral administration are, inter alia, preparations for injectionand infusion in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (inter alia powder inhalers, nebulizers), nasaldrops/solutions/sprays; tablets to be administered lingually,sublingually or buccally, films/wafers or capsules, suppositories,preparations for the eyes or ears, vaginal capsules, aqueous suspensions(lotions, shaking mixtures), lipophilic suspensions, ointments, creams,transdermal therapeutic systems (such as plasters, for example), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, nontoxic, pharmaceutically suitable adjuvants.These adjuvants include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (for exampleliquid polyethylene glycols), emulsifiers and dispersants or wettingagents (for example sodium dodecyl sulphate, polyoxysorbitan oleate),binders (for example polyvinylpyrrolidone), synthetic and naturalpolymers (for example albumin), stabilizers (for example antioxidants,such as, for example, ascorbic acid), colorants (for example inorganicpigments, such as, for example, iron oxides) and flavour- and/orodour-masking agents.

The present invention furthermore provides medicaments comprising atleast one compound according to the invention, usually together with oneor more inert, nontoxic, pharmaceutically suitable adjuvants, and theiruse for the purposes mentioned above.

When the compounds of the present invention are administered aspharmaceuticals, to humans or animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1% to 99.5% (morepreferably 0.5% to 90%) of active ingredient in combination with one ormore inert, nontoxic, pharmaceutically suitable adjuvants.

Regardless of the route of administration selected, the compoundsaccording to the invention of general formula (I) and/or thepharmaceutical composition of the present invention are fonnulated intopharmaceutically acceptable dosage forms by conventional methods knownto those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient without being toxic to the patient.

Materials and Methods:

The percentage data in the following tests and examples are percentagesby weight unless otherwise indicated; parts are parts by weight. Solventratios, dilution ratios and concentration data of liquid/liquidsolutions are in each case based on volume.

Examples were tested in selected biological and/or physicochemicalassays one or more times. When tested more than once, data are reportedas either average values or as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological or physicochemical assays represent averagevalues or median values calculated utilizing data sets obtained fromtesting of one or more synthetic batch.

The in vitro pharmacological, pharmacokinetic and physicochemicalproperties of the compounds can be determined according to the followingassays and methods.

Noteworthily, in the CDK9 assays described below the resolution power islimited by the enzyme concentrations, the lower limit for IC₅₀s is about1-2 nM in the CDK9 high ATP assay and 2-4 nM in the CDK low ATP assays.For compounds exhibiting IC₅₀s in this range the true affinity to CDK9and thus the selectivity for CDK9 over CDK2 might be even higher, i.e.for these compounds the selectivity factors calculated in columns 4 and7 of Table 2, infra, are minimal values, they could be also higher.

1a. CDK9/CycT1 Kinase Assay:

CDK9/CycT1-inhibitory activity of compounds of the present invention wasquantified employing the CDK9/CycT1 TR-FRET assay as described in thefollowing paragraphs:

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchased from Invitrogen (Cat. No PV4131). As substrate for the kinasereaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus inamid form) was used which can be purchased e.g. from the company JERINIPeptide Technologies (Berlin, Germany). For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipettedinto a black low volume 384 well microtiter plate (Greiner Bio-One,Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 in aqueousassay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl₂, 1.0 mM dithiothreitol,0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] wereadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of adenosine-tri-phosphate (ATP, 16. μM=> final conc.in the 5 μl assay volume is 10 μM) and substrate (1.67 μM=> final conc.in the 5 μl assay volume is 1 μM) in assay buffer and the resultingmixture was incubated for a reaction time of 25 min at 22° C. Theconcentration of CDK9/CycT1 was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 1 μg/mL. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan in house software.

1b. CDK9/CycT1 High ATP Kinase Assay

CDK9/CycT1-inhibitory activity of compounds of the present invention ata high ATP concentration after preincubation of enzyme and testcompounds was quantified employing the CDK9/CycT1 TR-FRET assay asdescribed in the following paragraphs.

Recombinant full-length His-tagged human CDK9 and CycT1, expressed ininsect cells and purified by Ni-NTA affinity chromatography, werepurchase from Invitrogen (Cat. No PV4131). As substrate for the kinasereaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus inamid form) was used which can be purchased e.g. from the company JERINIpeptide technologies (Berlin, Germany). For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipettedinto a black low volume 384 well microtiter plate (Greiner Bio-One,Frickenhausen, Germany), 2 μl of a solution of CDK9/CycT1 in aqueousassay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl₂, 1.0 mM dithiothreitol,0.1 mM sodium ortho-vanadate, 0.010% (v/v) Nonidet-P40 (Sigma)] wereadded and the mixture was incubated for 15 min at 22° C. to allowpre-binding of the test compounds to the enzyme before the start of thekinase reaction. Then the kinase reaction was started by the addition of3 μl of a solution of adenosine-tri-phosphate (ATP, 3.3 mM=> finalconec. in the 5 μl assay volume is 2 mM) and substrate (1.67 μM=> finalconc. in the 5 μl assay volume is 1 μM) in assay buffer and theresulting mixture was incubated for a reaction time of 25 min at 22° C.The concentration of CDK9/CycT1 was adjusted depending of the activityof the enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 0.5 μg/mL. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan in house software.

2a. CDK2/CycE Kinase Assay:

CDK2/CycE-inhibitory activity of compounds of the present invention wasquantified employing the CDK2/CycE TR-FRET assay as described in thefollowing paragraphs:

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchased fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. from the company JERINIPeptide Technologies (Berlin, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10mM MgCl₂, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01%(v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for15 min at 22° C. to allow pre-binding of the test compounds to theenzyme before the start of the kinase reaction. Then the kinase reactionwas started by the addition of 3 μl of a solution ofadenosine-tri-phosphate (ATP, 16.7 μM=> final conc. in the 5 μl assayvolume is 10 μM) and substrate (1.25 μM=> final conc. in the 5 μl assayvolume is 0.75 μM) in assay buffer and the resulting mixture wasincubated for a reaction time of 25 min at 22° C. The concentration ofCDK2/CycE was adjusted depending of the activity of the enzyme lot andwas chosen appropriate to have the assay in the linear range, typicalconcentrations were in the range of 130 ng/mL. The reaction was stoppedby the addition of 5 μl of a solution of TR-FRET detection reagents (0.2μM streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nManti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and 1.2nM LANCE EU-W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, productno. AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v) bovineserum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm was measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

2b. CDK2/CycE High ATP Kinase Assay:

CDK2/CycE-inhibitory activity of compounds of the present invention at 2mM adenosine-tri-phosphate (ATP) was quantified employing the CDK2/CycETR-FRET (TR-FRET=Time Resolved Fluorescence Resonance Energy Transfer)assay as described in the following paragraphs.

Recombinant fusion proteins of GST and human CDK2 and of GST and humanCycE, expressed in insect cells (Sf9) and purified byGlutathion-Sepharose affinity chromatography, were purchase fromProQinase GmbH (Freiburg, Germany). As substrate for the kinase reactionbiotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amidform) was used which can be purchased e.g. from the company JERINIpeptide technologies (Berlin, Germany).

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of asolution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10mM MgCl₂, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01%(v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for15 min at 22° C. to allow pre-binding of the test compounds to theenzyme before the start of the kinase reaction. Then the kinase reactionwas started by the addition of 3 μl of a solution ATP (3.33 mM=> finalconc. in the 5 μl assay volume is 2 mM) and substrate (1.25 μM=> finalconc. in the 5 μl assay volume is 0.75 μM) in assay buffer and theresulting mixture was incubated for a reaction time of 25 min at 22° C.The concentration of CDK2/CycE was adjusted depending of the activity ofthe enzyme lot and was chosen appropriate to have the assay in thelinear range, typical concentrations were in the range of 15 ng/ml. Thereaction was stopped by the addition of 5 μl of a solution of TR-FRETdetection reagents (0.2 μM streptavidine-XL665 [Cisbio Bioassays,Codolet, France] and 1 nM anti-RB(pSer807/pSer811)-antibody from BDPharmingen [#558389] and 1.2 nM LANCE EU-W1024 labeled anti-mouse IgGantibody [Perkin-Elmer, product no. AD0077, as an alternative aTerbium-cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassayscan be used]) in an aqueous EDTA-solution (100 mM EDTA, 0.2% (w/v)bovine serum albumin in 100 mM HEPES pH 7.5).

The resulting mixture was incubated 1 h at 22° C. to allow the formationof complex between the phosphorylated biotinylated peptide and thedetection reagents. Subsequently the amount of phosphorylated substratewas evaluated by measurement of the resonance energy transfer from theEu-chelate to the streptavidine-XL. Therefore, the fluorescenceemissions at 620 nm and 665 nm after excitation at 350 nm wer measuredin a TR-FRET reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg,Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665nm and at 622 nm was taken as the measure for the amount ofphosphorylated substrate. The data were normalised (enzyme reactionwithout inhibitor=0% inhibition, all other assay components but noenzyme=100% inhibition). Usually the test compounds were tested on thesame microtiterplate in 11 different concentrations in the range of 20μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8nM, 1.1 nM, 0.33 nM and 0.1 nM, the dilution series prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions) in duplicate values for eachconcentration and IC₅₀ values were calculated by a 4 parameter fit usingan inhouse software.

3. Proliferation Assay:

Cultivated tumour cells (HeLa, human cervical tumour cells, ATCC CCL-2;NCI—H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU145, hormone-independent human prostate carcinoma cells, ATCC HTB-81;HeLa-MaTu-ADR, multidrug-resistant human cervical carcinoma cells,EPO-GmbH Berlin; Caco-2, human colorectal carcinoma cells, ATCC HTB-37;B16F10, mouse melanoma cells, ATCC CRL-6475) were plated at a density of3,500 cells/well (DU145), 3,000 cells/well (HeLa-MaTu-ADR), 1,500cells/well (NCI—H460), 3,000 cells/well (HeLa), 2,000 cells/well(Caco-2), or 1,000 cells/well (B16F10) in a 96-well multititer plate in150 μL of their respective growth medium supplemented 10% fetal calfserum. After 24 hours, the cells of one plate (zero-point plate) werestained with crystal violet (see below), the test substances were addedin various concentrations (0 μM, as well as in the range of 0.0001-10μM) employing HP Dispenser. The cells were incubated for 4 days in thepresence of test substances. Cell proliferation was determined bystaining the cells with crystal violet: the cells were fixed by adding20 μl/measuring point of an 11% glutaric aldehyde solution for 15minutes at room temperature. After three washing cycles of the fixedcells with water, the plates were dried at room temperature. The cellswere stained by adding 100 μl/measuring point of a 0.1% crystal violetsolution DU 145, Caco-2, HeLa (pH 4.5) B16F10, NCI—H460, HeLa-MaTu-ADR.After three washing cycles of the stained cells with water, the plateswere dried at room temperature. The dye was dissolved by adding 100 μlper measuring point of a 10% acetic acid solution. The extinction wasdetermined by photometry at a wavelength of 595/550/620 nm depending onthe intensity of coloration, usually at 595 nm. The change of cellnumber, in percent, was calculated by normalization of the measuredvalues to the extinction values of the zero-point plate (=0%) and theextinction of the untreated (0 μM) cells (=100%). The IC₅₀ values(inhibitory concentration at 50% of maximal effect) were determined bymeans of a 4 parameter fit.

MOLM-13 human acute myeloid leukemia cells (DSMZ ACC 554) and A2780,human ovarian carcinoma cells (ECACC #93112519) were seeded at a densityof 5,000 cells/well (MOLM-13), or 3,000 cells/well (A2780) in a 96-wellmultititer plate in 150 μL of growth medium supplemented 10% fetal calfserum. After 24 hours, cell viability of one plate (zero-point plate)was determined with the Cell Titer-Glo Luminescent Cell Viability Assay(Promega), whiletest compound was added to the wells of the other platesemploying HP Dispenser (final concentrations in the range of 0.0001-10μM and DMSO controls). Cell viability was assessed after 72-hourexposure with the Cell Titer-Glo Luminescent Cell Viability Assay(Promega). IC₅₀ values (inhibitory concentration at 50% of maximaleffect) were determined by means of a 4 parameter fit on measurementdata which were normalized to vehicle (DMSO) treated cells (=100%) andmeasurement readings taken immediately before compound exposure (=0%).

4. Equilibrium Shake Flask Solubility Assay:

4a) High Throughput Determination of Aqueous Drug Solubility (100 Mmolarin DMSO)

The high throughput screening method to determine aqueous drugsolubility is based on: Thomas Onofrey and Greg Kazan, Performance andcorrelation of a 96-well high throughput screening method to determineaqueous drug solubility,http://wwv.millipore.com/publications.nsf/a73664f9f981af8c852569b9005b4eee/e565516fb76e743585256da30052db77/$FILE/AN1731EN00.pdf

The assay was run in a 96-well plate format. Each well was filled withan individual compound.

All pipetting steps were performed using a robot platform.

100 μl of a 10 mmolar solution of drug in DMSO were concentrated byvacuum centrifugation and resolved in 10 μl DMSO. 990 μl phosphatebuffer pH 6.5 were added. The content of DMSO amounts to 1%. Themultititer plate was put on a shaker and mixed for 24 hrs at roomtemperature. 150 μl of the suspension were transferred to a filtrationplate. After filtration using a vacuum manifold the filtrate was diluted1:400 and 1:8000. A second microtiter plate with 20 μl of a 10 mMsolution of drug in DMSO served for calibration. Two concentrations(0.005 μM and 0.0025 μM) were prepared by dilution in DMSO/water 1:1 andused for calibration. Filtrate and calibration plates were quantified byHPLC-MS/MS.

Chemicals:

Preparation of 0.1 m phosphate buffer pH 6.5:

61.86 g NaCl and 39.54 mg KH₂PO₄ were solved in water and filled up to 1l. The mixture was diluted 1:10 with water and the pH adjusted to 6.5 byNaOH.

Materials:

Millipore MultiScreenH_(T)s-HV Plate 0.45 μm

Chromatographic conditions were as follows:

HPLC column: Ascentis Express C18 2.7 μm 4.6×30 mm

Injection volume: 1 μl

Flow: 1.5 ml/min

Mobile phase: acidic gradient

-   -   A: Water/0.05% HCOOH    -   B: Acetonitrile/0.05% HCOOH    -   0 min→95% A 5% B    -   0.75 min→5% A 95% B    -   2.75 min→5% A 95% B    -   2.76 min→95% A 5% B    -   3 min→95% A 5% B

The areas of sample- and calibration injections were determined by usingmass spectromety software (AB SCIEX: Discovery Quant 2.1.3. and Analyst1.6.1). The calculation of the solubility value (in mg/l) was executedby an inhouse developed Excel macro.

4b) Thermodynamic Solubility in Water from Powder

The thermodynamic solubility of compounds in water was determined by anequilibrium shake flask method (see for example: E. H. Kerns, L. Di:Drug-like Properties: Concepts, Structure Design and Methods, 276-286,Burlington, Mass., Academic Press, 2008). A saturated solution of thedrug was prepared and the solution was mixed for 24 h to ensure thatequilibrium was reached. The solution was centrifuged to remove theinsoluble fraction and the concentration of the compound in solution wasdetermined using a standard calibration curve. To prepare the sample, 2mg solid compound was weighed in a 4 mL glass vial. 1 mL phosphatebuffer pH 6.5 was added. The suspension was stirred for 24 hrs at roomtemperature. The solution was centrifuged afterwards. To prepare thesample for the standard calibration, 2 mg solid sample was dissolved in30 mL acetonitrile. After sonification the solution was diluted withwater to 50 mL. Sample and standards were quantified by HPLC withUV-detection. For each sample two injection volumes (5 and 50 μl) intriplicates were made. Three injection volumes (5 μl, 10 μl and 20 μl)were made for the standard.

Chromatographic Conditions:

-   HPLC column: Xterra MS C18 2.5 μm 4.6×30 mm-   Injection volume: Sample: 3×5 μl and 3×50 μl    -   Standard: 5 μl, 10 μl, 20 μl-   Flow: 1.5 mL/min-   Mobile phase: acidic gradient:    -   A: Water/0.01% TFA    -   B: Acetonitrile/0.01% TFA    -   0 min→95% A 5% B    -   0-3 min→35% A 65% B, linear gradient    -   3-5 min→35% A 65% B, isocratic    -   5-6 min→95% A 5% B, isocratic-   UV detector: wavelength near the absorption maximum (between 200 and    400 nm)

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/l) were determined by using HPLC software(Waters Empower 2 FR).

4c) Thermodynamic Solubility in Citrate Buffer pH 4

Thermodynamic solubility was determined by an equilibrium shake flaskmethod [Literature: Edward H.

Kerns and Li Di (2008) Solubility Methods in: Drug-like Properties:Concepts, Structure Design and Methods, p 276-286. Burlington, Mass.:Academic Press].

A saturated solution of the drug was prepared and the solution was mixedfor 24 h to ensure that equilibrium has been reached. The solution wascentrifuged to remove the insoluble fraction and the concentration ofthe compound in solution was determined using a standard calibrationcurve.

To prepare the sample, 1.5 mg solid compound was weighed in a 4 ml glassvial. 1 ml Citrate buffer pH 4 was added. The suspension was put on astirrer and mixed for 24 hrs at room temperature. The solution wascentrifuged afterwards. To prepare the sample for the standardcalibration, 0.6 mg solid sample was dissolved in 19 mlacetonitrile/water 1:1. After sonification the solution was filled upwith acetonitrile/water 1:1 to 20 ml.

Sample and standards were quantified by HPLC with UW-detection. For eachsample two injection volumes (5 and 50 μl) in triplicates were made.Three injection volumes (5 μl, 10 μl and 20 μl) were made for thestandard.

Chemicals:

Citrate buffer pH 4 (MERCK Art. 109435; 1 L buffer consisting of 11,768g citric acid, 4,480 g sodium hydroxide, 1,604 g hydrogen chloride)

Chromatographic conditions were as follows:

-   HPLC column: Xterra MS C18 2.5 μm 4.6×30 mm-   Injection volume: Sample: 3×5 μl and 3×50 μl    -   Standard: 5 μl, 10 μl, 20 μl-   Flow: 1.5 ml/min-   Mobile phase: acidic gradient:    -   A: Water/0.01% TFA    -   B: Acetonitrile/0.01% TFA    -   0 min: 95% A 5% B    -   0-3 min: 35% A 65% B, linear gradient    -   3-5 min: 35% A 65% B, isocratic    -   5-6 min: 95% A 5% B, isocratic        UV detector: wavelength near the absorption maximum (between 200        and 400 nm)

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/l) were determined by using HPLC software(Waters Empower 2 FR).

The areas of sample- and standard injections as well as the calculationof the solubility value (in mg/l) were determined by using HPLC software(Waters Empower 2 FR).

5. Caco-2 Permeation Assay:

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×10⁴ cells per well on 24 well insert plates, 0.4 m poresize, and grown for 15 days in DMEM medium supplemented with 10% fetalbovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/mL penicillin, 100 μg/mLstreptomycin (GIBCO) and 1% non essential amino acids (100×). Cells weremaintained at 37° C. in a humified 5% CO₂ atmosphere. Medium was changedevery 2-3 day. Before running the permeation assay, the culture mediumwas replaced by a FCS-free hepes-carbonate transport buffer (pH 7.2).For assessment of monolayer integrity the transepithelial electricalresistance (TEER) was measured. Test compounds were predissolved in DMSOand added either to the apical or basolateral compartment in finalconcentration of 2 μM in transport buffer. Before and after 2 hincubation at 37° C. samples were taken from both compartments. Analysisof compound content was done after precipitation with methanol byLC/MS/MS analysis. Permeability (Papp) was calculated in the apical tobasolateral (A→B) and basolateral to apical (B→A) directions. Theapparent permeability was calculated using following equation:Papp=(Vr/Po)(1/S)(P2/t)Where Vr is the volume of medium in the receiver chamber, Po is themeasured peak area or height of the test drug in the donor chamber att=o, S the surface area of the monolayer, P2 is the measured peak areaof the test drug in the acceptor chamber after 2 h of incubation, and tis the incubation time. The efflux ratio basolateral (B) to apical (A)was calculated by dividing the Papp B-A by the Papp A-B. In addition thecompound recovery was calculated.6. Investigation of In Vitro Metabolic Stability in Rat Hepatocytes

Hepatocytes from Han Wistar rats were isolated via a 2-step perfusionmethod. After perfusion, the liver was carefully removed from the rat:the liver capsule was opened and the hepatocytes were gently shaken outinto a Petri dish with ice-cold Williams medium E (purchased from SigmaAldrich Life Science, St Louis, Mo.). The resulting cell suspension wasfiltered through sterile gaze in 50 ml falcon tubes and centrifuged at50×g for 3 min at room temperature. The cell pellet was resuspended in30 ml WME and centrifuged through a Percoll® gradient for 2 times at100×g. The hepatocytes were washed again with Williams' medium E (WME)and resuspended in medium containing 5% Fetal calf serum (FCS, purchasedfrom Invitrogen, Auckland, NZ). Cell viability was determined by trypanblue exclusion. For the metabolic stability assay liver cells weredistributed in WME containing 5% FCS to glass vials at a density of1.0×10⁶ vital cells/ml. The test compound was added to a finalconcentration of 1 μM. During incubation, the hepatocyte suspensionswere continuously shaken and aliquots were taken at 2, 8, 16, 30, 45 and90 min, to which equal volumes of cold acetonitrile were immediatelyadded. Samples were frozen at −20° C. over night, after subsequentlycentrifuged for 15 minutes at 3000 rpm and the supernatant was analyzedwith an Agilent 1200 HPLC-system with LCMS/MS detection.

The half-life of a test compound was determined from theconcentration-time plot. From the half-life the intrinsic clearanceswere calculated. Together with the additional parameters liver bloodflow, amount of liver cells in vivo and in vitro, the maximal oralbioavailability (Fmax) was calculated using the following scalingparameters: Liver blood flow (rat)—4.2 L/h/kg; specific liver weight—32μg/kg rat body weight; liver cells in vivo—1.1×10⁸ cells/g liver, livercells in vitro—0.5×10⁶/ml.

7. In Vivo Pharmacokinetics in Rats

For in vivo pharmacokinetic experiments test compounds were administeredto male Wistar rats intravenously at doses of 0.3 to 1 mg/kg formulatedas solutions using either rat plasma or solubilizers such as PEG400 inwell-tolerated amounts.

For pharmacokinetics after intravenous administration test compoundswere given as i.v. bolus and blood samples were taken at 2 min, 8 min,15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after dosing.Depending on the expected half-life additional samples were taken atlater time points (e.g. 48 h, 72 h). Blood was collected intoLithium-Heparin tubes (Monovetten®, Sarstedt) and centrifuged for 15 minat 3000 rpm. An aliquot of 100 μL from the supernatant (plasma) wastaken and precipitated by addition of 400 μL ice cold acetonitrile andfrozen at −20° C. over night. Samples were subsequently thawed andcentrifuged at 3000 rpm, 4° C. for 20 minutes. Aliquots of thesupernatants were taken for analytical testing using an Agilent 1200HPLC-system with LCMS/MS detection. PK parameters were calculated bynon-compartmental analysis using a PK calculation software.

PK parameters derived from concentration-time profiles after i.v.:CLplasma: Total plasma clearance of test compound (in L/kg/h); CLblood:Total blood clearance of test compound: CLplasma*Cp/Cb (in L/kg/h) withCp/Cb being the ratio of concentrations in plasma and blood, AUCnorm:Area under the concentration-time curve from t=0 h to infinity(extrapolated) divided by the administered dose (in kg*h/L); t_(1/2):terminal half-life (in h).

8. Surface Plasmon Resonance PTEFb

DEFINITIONS

The term “surface plasmon resonance”, as used herein, refers to anoptical phenomenon that allows for the analysis of the reversibleassociations of biological molecules in real time within a biosensormatrix, for example using the Biacore® system (GE HealthcareBiosciences, Uppsala, Sweden). Biacore® uses the optical properties ofsurface plasmon resonance (SPR) to detect alterations in the refractiveindex of a buffer, which changes as molecules in solution interact withthe target immobilized on the surface. In brief, proteins are covalentlybound to the dextran matrix at a known concentration and a ligand forthe protein is injected through the dextran matrix. Near infrared light,directed onto the opposite side of the sensor chip surface is reflectedand also induces an evanescent wave in the gold film, which in turn,causes an intensity dip in the reflected light at a particular angleknown as the resonance angle. If the refractive index of the sensor chipsurface is altered (e.g. by compound binding to the bound protein) ashift occurs in the resonance angle. This angle shift can be measured.These changes are displayed with respect to time along the y-axis of asensorgram, which depicts the association and dissociation of anybiological reaction.

The term “K_(D)”, as used herein, is intended to refer to theequilibrium dissociation constant of a particular compound/targetprotein complex.

The term “k_(off)”, as used herein, is intended to refer to theoff-rate, i.e. the dissociation rate constant of a particularcompound/target protein complex.

The term “target residence time”, as used herein, is intended to referto the inverse of the rate of dissociation rate constant (1/k_(off)) ofa particular compound/target protein complex.

For further descriptions see:

Jönsson U et al al., 1993 Ann Biol Clin.; 51(1):19-26.

Johnsson B et al, Anal Biochem. 1991; 198(2):268-77.

Day Y et al, Protein Science, 2002; 11, 1017-1025

Myskza D G, Anal Biochem., 2004; 329, 316-323

Tummino and Copeland, Biochemistry, 2008; 47(20):5481-5492.

Biological Activity

The biological activity (e.g. as inhibitors of PETFb) of the compoundsaccording to the invention can be measured using the SPR assaydescribed.

The level of activity exhibited by a given compound in the SPR assay canbe defined in terms of the K_(D) value, and preferred compounds of thepresent invention are compounds having a K_(D) value of less than 1micromolar, more preferably less than 0.1 micromolar.

Furthermore, the time in residence at its target of a given compound canbe defined in terms of the target residence time (TRT), and preferredcompounds of the present invention are compounds having a TRT value ofmore than 10 minutes, more preferably more than 1 hour.

The ability of the compounds according to the invention to bind humanPTEFb may be determined using surface plasmon resonance (SPR). K_(D)values and k_(off) values may be measured using a Biacoret T200instrument (GE Healthcare, Uppsala, Sweden).

For SPR measurements, recombinant human PTEFb (CDK9/Cyclin T1recombinant human active protein kinase purchased from ProQinase,Freiburg, Germany) is immobilized using standard amine coupling(Johnsson B et al, Anal Biochem. 1991 Nov. 1; 198(2):268-77). Briefly,carboxymethylated dextran biosensor chips (CM7, GE Healthcare) areactivated with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to thesupplier's instructions. Human PTEFb is diluted in 1×HBS-EP+(GEHealthcare) into 30 μg/ml and injected on the activated chip surface.Subsequently, a 1:1 solution of 1 M ethanolamine-HCl (GE Healthcare) and1×HBS-EP is injected to block unreacted groups, resulting inapproximately 4000 response units (RU) of immobilized protein. Areference surface is generated by treatment with NHS-EDC andethanolamine-HCl. Compounds are dissolved in 100% dimethylsulfoxide(DMSO, Sigma-Aldrich, Germany) to a concentration of 10 mM andsubsequently diluted in running buffer (1×HBS-EP+pH 7.4 [generated fromHBS-EP+Buffer 10×(GE Healthcare): 0.1 M HEPES, 1.5 M NaCl, 30 mM EDTAand 0.5% v/v Surfactant P20], 1% v/v DMSO). For kinetic measurements,four-fold serial dilutions of compound (0.39 nM to 100 nM) are injectedover immobilized protein. Binding kinetics is measured at 25° C. with aflow rate of 50 μl/min in running buffer. Compound concentrations areinjected for 60 s followed by a dissociation time of 1800 s. Slightvariations of these parameters are indicated in Table 6a and 6b. SPRmeasurements performed at 37° C. are summarized in Table 6b. Theresulting sensorgrams are double-referenced against the referencesurface as well as against blank injections.

The double-referenced sensorgrams are fit to a simple reversibleLangmuir 1:1 reaction mechanism as implemented in the Biacore® T200evaluation software 2.0 (GE Healthcare). In cases were full compounddissociation has not occurred at the end of the dissociation phase, theRmax parameter (response at saturation) is fit as local variable. In allother cases, Rmax is fit as global variable.

Syntheses of Compounds

The syntheses of the macrocyclic compounds of formula (I) according tothe present invention are preferably carried out according to thegeneral synthetic sequences as shown in Schemes 1a, 1b, 1c, 1d, 2, 3a,3b, 3c, 4 and 5.

In addition to said routes described below, also other routes may beused to synthesise the target compounds, in accordance with commongeneral knowledge of a person skilled in the art of organic synthesis.The order of transformations exemplified in the following Schemes istherefore not intended to be limiting, and suitable synthesis steps fromvarious schemes can be combined to form additional synthesis sequences.In addition, modification of any of the substituents R¹, R², R³, R⁴and/or R⁵ can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotective groups, cleavage of protective groups, reduction or oxidationof functional groups, halogenation, metallation, metal catalysedcoupling reactions, substitution or other reactions known to a personskilled in the art. These transformations include those which introducea functionality allowing for further interconversion of substituents.Appropriate protective groups and their introduction and cleavage arewell-known to a person skilled in the art (see for example T. W. Greeneand P. G. M. Wuts in Protective Groups in Organic Synthesis, 4^(th)edition, Wiley 2006). Specific examples are described in the subsequentparagraphs. Further, it is possible that two or more successive stepsmay be performed without work-up being performed between said steps,e.g. a “one-pot” reaction, as it is well-known to a person skilled inthe art.

The geometry of the sulfondiimine moiety renders some of the compoundsof the general formula (I) chiral. Separation of racemic sulfondiiminesinto their enantiomers can be achieved by methods known to the personskilled in the art, preferably by means of preparative HPLC on chiralstationary phase.

The syntheses of the pyridine derivatives of formula (10), constitutinga subset of the general formula (I) according to the present invention,are preferably carried out according to the general synthetic sequencesas shown in Schemes 1a, 1b, 1c and 1d.

Schemes 1a, 1b and 1c, wherein L, R¹, R², R³, R⁴ and R⁵ are as definedfor the compound of general formula (I) according to the presentinvention, outline the preparation of pyridine-based macrocycliccompounds of formula (10), from 2-chloro-5-fluoro-4-iodopyridine (1; CAS#884494-49-9). Said starting material (1) is reacted with a boronic acidderivative of formula (2), in which R³ and R⁴ are as defined for thecompound of general formula (I), to give a compound of formula (3). Theboronic acid derivative (2) may be a boronic acid (R═—H) or an ester ofthe boronic acid, e.g. its isopropyl ester (R═—CH(CH₃)₂), preferably anester derived from pinacol in which the boronic acid intermediate formsa 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(R—R═—C(CH₃)₂—C(CH₃)₂—).

Said coupling reaction is catalyzed by palladium catalysts, e.g. byPd(0) catalysts such as tetrakis(triphenylphosphine)palladium(0)[Pd(PPh₃)₄], tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], orby Pd(II) catalysts such asdichlorobis(triphenylphosphine)-palladium(II) [Pd(PPh₃)₂Cl₂],palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction is preferably carried out in a mixture of a solvent such as1,2-dimethoxyethane, dioxane, DMF, THF, or isopropanol with water and inthe presence of a base such as potassium carbonate, sodium bicarbonateor potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction is performed at temperatures ranging from room temperature(i.e. approx. 20° C.) to the boiling point of the respective solvent.Further on, the reaction can be performed at temperatures above theboiling point using pressure tubes and a microwave oven. The reaction ispreferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (3) is converted to a compoundof formula (4). This reaction can be carried out by aPalladium-catalyzed C—N cross-coupling reaction (for a review on C—Ncross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere,F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004). Preferred isthe herein described use of lithium bis(trimethylsilyl)amide,tris(dibenzylideneacetone)dipalladium(0) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl in THF. Thereactions are preferably run under an atmosphere of argon for 3-24 hoursat 40-80° C. in an oil bath.

In the third step, a compound of formula (4) is converted to a compoundof formula (5), by means of cleaving the methyl ether present incompounds of formula (4).

Preferred is the herein described use of boron tribromide in DCM. Thereactions are preferably run for 1-24 hours at 0° C. to roomtemperature.

In the fourth step, a compound of formula (5) is coupled with a compoundof formula (6), in which R¹, R² and L are as defined for the compound ofgeneral formula (I), to give a compound of formula (7), in the presenceof a tertiary phosphine, such as triphenylphosphine, and a dialkyldiazodicarboxylate (known as Mitsunobu reaction, see for example: K. C.K. Swamy et al, Chem. Rev. 2009, 109, 2551). Preferred is the hereindescribed use of diisopropyl azodicarboxylate and triphenylphosphine inTHF. The reactions are preferably run for 1-24 hours at 0° C. to roomtemperature.

Compounds of the formula (6) can be prepared as outlined in Scheme 2,infra.

In the fifth step, a compound of formula (7) is converted to amacrocycle of formula (8). This cyclization reaction can be carried outby an intramolecular Palladium-catalyzed C—N cross-coupling reaction(for a review on C—N cross coupling reactions see for example: a) L.Jiang, S. L. Buchwald in ‘Metal-Catalyzed Cross-Coupling Reactions’,2^(nd) ed.: A. de Meijere, F. Diederich, Eds.: Wiley-VCH: Weinheim,Germany, 2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst andligand, an alkali carbonate or an alkali phosphate, preferably potassiumphosphate, as a base, in a mixture of a C₁-C₃-alkylbenzene and acarboxamide based solvent, preferably a mixture of toluene and NMP, as asolvent. The reactions are preferably run under an atmosphere of argonfor 2-24 hours at 100-130° C. in a microwave oven or in an oil bath.

As shown in Scheme 1d, macrocyclic compounds of formula (8a), whichconstitutes a sub-compartment of formula (8) in that R² of formula (8)represents a hydrogen atom, can be advantageously used for theintroduction of R² groups different from a hydrogen atom, e.g. byreacting a compound of formula (8a), in which R¹, R³, R⁴ and L are asdefined for the compound of general formula (I) according to the presentinvention, with N-iodosuccinimide, in a carboxamide based solvent suchas DMF, to give iodinated intermediates of formula (8b), which in turncan be converted into compounds of formula (8c), in which R² is asdefined for the compound of general formula (I) but different from ahydrogen atom, by methods known to the person skilled in the art,exemplified by but not limited to the conversion of a compound offormula (8b) into the corresponding carbonitrile (R²═CN) by reactionwith copper(I)cyanide in DMSO, at a temperature between 100° C. and 160°C.

In the sixth step, and as shown in Scheme 1c, supra, a sulfide offormula (8) is converted to a compound of formula (9), by treatment withO-(mesitylenesulfonyl) hydroxylamine (MSH), in an inert solvent, such asa chlorinated aliphatic hydrocarbon of the formula chloro-C₁-C₂-alkyl-H,more preferably dichloromethane, at a temperature between −20° C. and80° C., preferably between −10° C. and 60° C., more preferably between0° C. and 40° C. (see for example: C. Bolm et al, Angew. Chem. 2012,124, 4516).

In the final step, a compound of formula (9) is converted to a compoundof formula (I) in a one-pot sequence by oxidation withN-chlorosuccinimide (NCS), in a carboxamide as a solvent, preferablyN,N-dimethylformamide (DMF), N,N-dimethylacetamide orN-methylpyrrolidin-2-one (NMP) or a mixture thereof, more preferablyN,N-dimethylformamide (DMF), in the presence of an alkali carbonate,preferably sodium carbonate as a base, followed by the addition of aprimary amine of the formula R⁵⁻NH₂, wherein R⁵ is as defined for thecompound of general formula (I), or hexamethyldisilazane in case R⁵ inthe reaction product represents a hydrogen atom, at a temperaturebetween −20° C. and 50° C., preferably between −10° C. and 40° C., morepreferably between 0° C. and 30° C. (see for example: C. Bolm et al,Angew. Chem. 2012, 124, 4516).

Alternatively, iodobenzene diacetate can be used instead of NCS.Preferably, the reaction is run in a chlorinated aliphatic hydrocarbonof the formula chloro-C₁-C₂-alkyl-H, more preferably dichloromethane, asa solvent, if iodobenzene diacetate is used instead of NCS.

Compounds of the formula (6), in which R¹, R² and L are as defined forthe compound of general formula (I) according to the present invention,can be prepared according to Scheme 2, starting e.g. from a2,6-dichloroisonicotinic acid derivative of formula (11), in which R² isas defined for the compound of general formula (I), which is reduced tothe corresponding pyridinemethanol of formula (12), by means ofreduction. Preferred is the herein described use ofsulfanediyldimethane-borane (1:1 complex) in tetrahydrofuran.

Derivatives of isonicotinic acid of formula (11), and esters thereof,are well known to the person skilled in the art, and are oftencommercially available.

In a second step, pyridinemethanol of formula (12) is reacted to give acompound of formula (13), in which LG represents a leaving group such aschloro, bromo, iodo, C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-,benzenesulfonyloxy-, or para-toluenesulfonyloxy-. Such conversions arewell known to the person skilled in the art; preferred is the hereindescribed use of methanesulfonyl chloride in the presence oftriethylamine as a base, in dichloromethane as a solvent, to give acompound of formula (13) in which LG represents methanesulfonyloxy-.

In a third step, a compound of formula (13) is reacted with a thiol ofthe formula R¹—SH (or a salt thereof), in which R¹ is as defined for thecompound of general formula (I), optionally in the presence of a basesuch as sodium hydroxide, to give a thioether derivative of formula(14). Thiols of the formula R¹SH and their salts are well known to theperson skilled in the art and are commercially available in considerablevariety.

In a fourth step, a thioether derivative of formula (14) is reacted witha anion formed in situ from a diol of the formula HO-L-OH, in which L isas defined for the compound of general formula (I), and an alkali metal,preferably sodium, in tetrahydrofuran as a solvent, to give intermediatecompounds of formula (6) which can be further processed as outlined inSchemes 1b and 1c.

The syntheses of the pyrimidine derivatives of formula (23),constituting a further sub-set of the general formula (I) according tothe present invention, are preferably carried out according to thegeneral synthetic sequences as shown in Schemes 3a, 3b and 3c.

Schemes 3a, 3b and 3c, wherein L, R¹, R², R³, R⁴ and R⁵ are as definedfor the compound of general formula (I) according to the presentinvention, outline the preparation of pyrimidine compounds of thegeneral formula (I) from 2,4-dichloro-5-fluoropyrimidine (CAS#2927-71-1,15). Said starting material (15) is reacted with a boronicacid derivative of formula (2) to give a compound of formula (16). Theboronic acid derivative (2) may be a boronic acid (R═—H) or an ester ofthe boronic acid, e.g. its isopropyl ester (R═—CH(CH₃)₂), preferably anester derived from pinacol in which the boronic acid intermediate formsa 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(R—R═—C(CH₃)₂—C(CH₃)₂—). Boronic acids and their esters are commerciallyavailable and well-known to the person skilled in the art; see e.g. D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim,ISBN 3-527-30991-8 and references cited therein.

The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0)catalysts such as tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts such as dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride[Pd(dppf)Cl₂].

The reaction is preferably carried out in a mixture of a solvent such as1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with waterand in the presence of a base such as aqueous potassium carbonate,aqueous sodium bicarbonate or potassium phosphate.

The reaction is performed at temperatures ranging from room temperature(=20° C.) to the boiling point of the solvent. Further on, the reactioncan be performed at temperatures above the boiling point using pressuretubes and a microwave oven. (review: D. G. Hall, Boronic Acids, 2005WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 andreferences cited therein).

The reaction is preferably completed after 1 to 36 hours of reactiontime.

In the second step, a compound of formula (16) is converted to acompound of formula (17). Preferred is the herein described use of borontribromide in DCM. The reactions are preferably run for 1-24 hours at 0°C. to room temperature.

In the third step, a compound of formula (17) is coupled with a compoundof formula (18) to give a compound of formula (19)), in the presence ofa tertiary phosphine, such as triphenylphosphine, and a dialkyldiazodicarboxylate (known as Mitsunobu reaction, see for example: K. C.K. Swamy et al, Chem. Rev. 2009, 109, 2551).

Preferred is the herein described use of diisopropyl azodicarboxylateand triphenylphosphine in tetrahydrofuran or dichloromethane. Thereactions are preferably run for 1-24 hours at 0° C. to roomtemperature.

Compounds of formula (19) can be reduced to give anilines of formula(20). The reduction can be prepared analogously to known processes (seefor example: (a) Sammond et al; Bioorg. Med. Chem. Lett. 2005, 15, 3519;(b) R. C. Larock, Comprehensive Organic Transformations, VCH, New York,1989, 411-415). Preferred is the herein described hydrogenation inmethanol and THF using platinum and vanadium on activated carbon as acatalyst.

A compound of formula (20) can be converted to a macrocycle of formula(21). This cyclization reaction can be carried out by aPalladium-catalyzed C—N cross-coupling reaction (for a review on C—Ncross coupling reactions see for example: a) L. Jiang, S. L. Buchwald in‘Metal-Catalyzed Cross-Coupling Reactions’, 2^(nd) ed.: A. de Meijere,F. Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).

Preferred is the herein described use ofchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl as catalyst andligand, an alkali carbonate or an alkali phosphate, preferably potassiumphosphate, as a base, in a mixture of a C₁-C₃-alkylbenzene and acarboxamide based solvent, preferably a mixture of toluene and NMP, as asolvent. The reactions are preferably run under an atmosphere of argonfor 2-24 hours at 100-130° C. in a microwave oven or in an oil bath.

A sulfide of formula (21) can be converted to a compound of formula(22), by treatment with O-(mesitylenesulfonyl) hydroxylamine (MSH), inan inert solvent, such as a chlorinated aliphatic hydrocarbon of theformula chloro-C₁-C₂-alkyl-H, more preferably dichloromethane, at atemperature between −20° C. and 80° C., preferably between −10° C. and60° C., more preferably between 0° C. and 40° C.

(see for example: C. Bolm et al, Angew. Chem. 2012, 124, 4516).

In the final step, a compound of formula (22) can be converted to acompound of formula (23) in a one-pot sequence by oxidation withN-chlorosuccinimide (NCS), in a carboxamide as a solvent, preferablyN,N-dimethylformamide (DMF), N,N-dimethylacetamide orN-methylpyrrolidin-2-one or a mixture thereof, more preferablyN,N-dimethylformamide (DMF), in the presence of an alkali carbonate,preferably sodium carbonate as a base, followed by the addition of aprimary amine of the formula R⁵—NH₂, wherein R⁵ is as defined for thecompound of general formula (I), or hexamethyldisilazane in case R⁵ inthe reaction product represents a hydrogen atom, at a temperaturebetween −20° C. and 50° C., preferably between −10° C. and 40° C., morepreferably between 0° C. and 30° C. (see for example: C. Bolm et al,Angew. Chem. 2012, 124, 4516).

Alternatively, iodobenzene diacetate can be used instead of NCS.Preferably, the reaction is run in a chlorinated aliphatic hydrocarbonof the formula chloro-C₁-C₂-alkyl-H, more preferably dichloromethane, asa solvent, if iodobenzene diacetate is used instead of NCS.

Compounds of the formula (18), in which R¹, R² and L are as defined forthe compound of general formula (I) according to the present invention,can be prepared according to Scheme 4, starting e.g. from a benzylicalcohol derivative of formula (24), in which R² is as defined for thecompound of general formula (I), is reacted to give a compound offormula (25), in which LG represents a leaving group such as chloro,bromo, iodo, C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-,benzenesulfonyloxy-, or para-toluenesulfonyloxy-. Such conversions arewell known to the person skilled in the art; preferred is the hereindescribed use of thionyl chloride in N,N-dimethylformamide (DMF) as asolvent, to give a compound of formula (25) in which LG representschloro.

Benzylic alcohol derivative of formula (24), or the correspondingcarboxylic acids and their esters, are known to the person skilled inthe art, and are commercially available in certain cases.

In a second step, a compound of formula (25) is reacted with a thiol ofthe formula R¹—SH (or a salt thereof), in which R¹ is as defined for thecompound of general formula (I), optionally in the presence of a basesuch as sodium hydroxide, to give a thioether derivative of formula(26). Thiols of the formula R¹SH and their salts are well known to theperson skilled in the art and are commercially available in considerablevariety.

In a third step, a thioether derivative of formula (26) is reacted witha carboxylic ester of formula (27), in which L′ represents aC₁-C₅-alkylene group featuring one carbon atom less as compared to thecorresponding group L in formula (28), L in turn being as defined forthe the compound of general formula (I), R^(E) represents a C₁-C₄-alkylgroup, and in which LG represents a leaving group such as chloro, bromo,iodo, C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-,benzenesulfonyloxy-, or para-toluenesulfonyloxy-, in the presence of abase, such as an alkali carbonate, preferably potassium carbonate, inN,N-dimethylformamide (DMF) as a solvent, to give a compound of formula(28).

In a fourth step, an ester of the formula (28) can be reduced using areducing agent such as lithium aluminium hydride ordi-iso-butylaluminiumhydride (DIBAL), in an ether, preferablytetrahydrofuran, as a solvent, to give compound of the formula (18)which can be further processed as shown in the Schemes 3a, 3b and 3c.

Alternatively, a thioether derivative of formula (26) can be directlyconverted into a compound of formula (18), if reacted with a compound ofthe formula HO-L-LG, in which L is as defined for the compound ofgeneral formula (I) according to the present invention, and in which LGrepresents a leaving group such as chloro, bromo, iodo,C₁-C₄-alkyl-S(═O)₂O—, trifluoromethanesulfonyloxy-, benzenesulfonyloxy-,or para-toluenesulfonyloxy-, instead of a compound of the formula (27),in the presence of a base, such as an alkali carbonate, preferablypotassium carbonate, in N,N-dimethylformamide (DMF) as a solvent.

Abbreviations Used in the Description of the Chemistry and in theExamples that Follow are:

br. (broad, ¹H NMR signal); CDCl₃ (deuterated chloroform); cHex(cyclohexane); DCE (dichloroethane); d (doublet, ¹H NMR signal); DCM(dichloromethane); DIBAL (di-iso-butylaluminiumhydride); DIPEA(di-iso-propylethylamine); DMAP (4-N,N-dimethylaminopyridine), DME(1,2-dimethoxyethane), DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); h(hour(s)); ¹H NMR (proton nuclear magnetic resonance spectroscopy); HPLC(High Performance Liquid Chromatography), iPrOH (iso-propanol); m(multiplet, ¹H NMR signal); mCPBA (meta-chloroperoxybenzoic acid), MeCN(acetonitrile), MeOH (methanol); min (minute(s)); MS (massspectrometry); MSH (O-(mesitylenesulfonyl) hydroxylamine); MTBE (methyltert-butyl ether); NCS (N-chloro succinimide); NMP(N-Methylpyrrolidin-2-one); NMR (nuclear magnetic resonance);Pd(dppf)Cl₂ ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane); q (quartet, ¹H NMR signal);quin (quintet, ¹H NMR signal); rac (racemic); RT (room temperature); s(singlet, ¹H NMR signal); sat. aq. (saturated aqueous); SiO₂ (silicagel); t (triplet, ¹H NMR signal); TFA (trifluoroacetic acid); TFAA(trifluoroacetic anhydride), THF (tetrahydrofuran); UPLC-MS (Ultra-HighPerformance Liquid Chromatography combined with Mass Spectrometry, usedfor reaction monitoring); UV (ultraviolet); wt-% (percent by weight).

¹H-NMR Spectra

¹H-NMR signals are specified with their multiplicity/combinedmultiplicities as apparent from the spectrum; possible higher-ordereffects are not considered. Chemical shifts of the signals (6) arespecified as ppm (parts per million).

Chemical Naming:

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

Salt Stoichiometry:

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Nd”, for example, are to be understood as not astoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

Preparative HPLC

Autopurifier: Acidic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% Vol. HCOOH (99%) B = MeCN Gradient: 0.00-0.50min 5% B, 25 ml/min 0.51-5.50 min 10-100% B, 70 ml/min 5.51-6.50 min100% B, 70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSOor DMF Injection: 1 × 2.5 ml Detection: DAD scan range 210-400 nm MSESI+, ESI−, scan range 160-1000 m/zAutopurifier: Basic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.2% Vol. NH₃ (32%) B = MeCN Gradient: 0.00-0.50 min5% B, 25 ml/min 0.51-5.50 min 10-100% B, 70 ml/min 5.51-6.50 min 100% B,70 ml/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or DMFInjection: 1 × 2.5 ml Detection: DAD scan range 210-400 nm MS ESI+,ESI−, scan range 160-1000 m/z

Example 115,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine

Preparation of Intermediate 1.1 (2,6-Dichloropyridin-4-yl)methanol

To a stirred solution 2,6-dichloroisonicotinic acid (10.0 g, 52.1 mmol)in THF (300 mL) at 0° C. was added a solution ofsulfanediyldimethane-borane (1:1) (16.0 g, 210.5 mmol) in THF. Themixture was allowed to react at room temperature overnight. Then MeOH(22 mL) was cautiously added to the stirred mixture while cooling withan ice bath. The reaction mixture was diluted with ethyl acetate (300mL), washed with an aqueous sodium hydroxide solution (1N, 100 mL) andsaturated aqueous sodium chloride solution. The organic layer wasconcentrated and the residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=7:1 to 3:1) to give desired titlecompound (8.3 g; 46.6 mmol).

¹H NMR (300 MHz, CDCl₃, 300K) δ=7.25 (2H); 4.72 (2H); 2.24 (1H).

Preparation of Intermediate 1.2 (2,6-dichloropyridin-4-yl)methylmethanesulfonate

(2,6-Dichloropyridin-4-yl)methanol (1.0 g; 5.62 mmol) was dissolved inDCM (20 mL) and triethyl amine (1.0 g; 9.88 mmol) was added. Theresulting mixture was cooled to 0° C. and methanesulfonyl chloride (0.9g, 7.89 mmol) was added. The mixture was stirred at room temperature for1 hour. By adding an aqueous hydrogen choride solution (1N), the pHvalue of the mixture was adjusted to 3, before it was extracted threetimes with ethyl acetate. The combined organic layers were concentratedto give the crude title compound (1.4 g) that was used without furtherpurification.

Preparation of Intermediate 1.32,6-Dichloro-4-[(methylsulfanyl)methyl]pyridine

(2,6-Dichloropyridin-4-yl)methyl methanesulfonate (1.40 g; 5.47 mmol)was dissolved in THF (20 mL) and a mixture of sodium thiomethoxide andsodium hydroxide (wt 1/1, 0.70 g, 5 mmol, supplied by Shanghai DEMOMedical Tech Co., Ltd) was added. The resulting mixture was stirredovernight at room temperature. The reaction mixture was diluted withwater (10 mL) and extracted three times with ethyl acetate. The combinedorganic layers were concentrated and the residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=6:1 to 3:1) to givethe desired title compound (0.54 g; 2.60 mmol).

¹H NMR (300 MHz, CDCl₃, 300K) δ=7.18 (2H), 3.55 (2H), 1.98 (3H).

Preparation of Intermediate 1.43-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)propan-1-ol

To a solution of 1,3-propanediol (660 mg; 8.68 mmol) in THF (10 mL) wasadded sodium (33 mg; 1.43 mmol) and the reaction mixture was heatedunder reflux for 3 hours. After cooling,2,6-dichloro-4-[(methylsulfanyl)methyl]pyridine (300 mg, 1.44 mmol) wasadded and the reaction mixture was heated under reflux for 16 hours.After cooling, the mixture was diluted with water (10 mL) and extractedthree times with ethyl acetate. The combined organic layers wereconcentrated and the residue was purified by flash column chromatographyon silica gel (hexane/ethyl acetate=5:1 to 2:1) to give the desiredtitle compound (180 mg; 0.72 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=6.86 (1H), 6.56 (1H), 4.42 (2H), 3.71(2H), 3.50 (2H), 3.27 (1H), 1.96 (5H).

Preparation of Intermediate 1.52-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine

A batch with 2-chloro-5-fluoro-4-iodopyridine (1000 mg; 3.88 mmol; APACPharmaceutical, LLC), (4-fluoro-2-methoxyphenyl)boronic acid (660 mg;3.88 mmol; Aldrich Chemical Company Inc.) andtetrakis(triphenylphosphin)palladium(0) (449 mg; 0.38 mmol) in1,2-dimethoxyethane (10.0 mL) and an aqueous 2 M solution of potassiumcarbonate (5.8 mL) was degassed using argon. The batch was stirred underan atmosphere of argon for 4 hours at 100° C. After cooling, the batchwas diluted with ethyl acetate and THF and washed with a saturatedaqueous solution of sodium chloride. The organic layer was filteredusing a Whatman filter and concentrated. The residue was purified bycolumn chromatography (hexane to hexane/ethyl acetate 50%) to give thedesired title compound (947 mg; 3.70 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.27 (m, 1H), 7.33 (m, 1H), 7.24 (m,1H), 6.75 (m, 2H), 3.83 (s, 3H).

Preparation of Intermediate 1.65-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine

A solution of lithium bis(trimethylsilyl)amide in THF (1M; 20.5 mL;20.53 mmol; Aldrich Chemical Company Inc.) was added to a mixture of2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridine (2.50 g; 9.78mmol; see Intermediate 1.5), tris(dibenzylideneacetone)dipalladium (0)(0.18 g; 0.20 mmol; Aldrich Chemical Company Inc.) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.19 g; 0.39mmol; Aldrich Chemical Company Inc.) in THF (16.3 mL) under anatmosphere of argon at room temperature. The mixture was stirred at 60°C. for 6 hours. The mixture was cooled to −40° C. and water (10 ml) wasadded. The mixture was slowly warmed to room temperature under stirring,solid sodium chloride was added and the mixture was extracted twice withethyl acetate. The combined organic layers were filtered using a Whatmanfilter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 60%) togive the desired title compound (2.04 g; 8.64 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=7.95 (1H), 7.20 (1H), 6.72 (2H), 6.46(1H), 4.33 (2H), 3.61 (3H).

Preparation of Intermediate 1.72-(2-Amino-5-fluoropyridin-4-yl)-5-fluorophenol

A solution of boron tribromide in DCM (1M; 47.1 mL; 47.1 mmol; AldrichChemical Company Inc.) was added dropwise to a stirred solution of5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyridin-2-amine (2.00 g; 8.47 mmol)in DCM (205 mL) at 0° C. The mixture was slowly warmed to roomtemperature while stirring overnight. The mixture was cautiously dilutedwith an aqueous solution of sodium bicarbonate under stirring at 0° C.and stirred at room temperature for 1 hour. A saturated solution ofsodium chloride was added and the mixture was extracted with ethylacetate. The combined organic layers were filtered using a Whatmanfilter and concentrated to give the crude title compound (1.92 g) thatwas used without further purification.

¹H NMR (400 MHz, DMSO-d6, 300K) δ=10.21 (1H), 7.84 (1H), 7.19 (1H), 6.71(2H), 6.39 (1H), 5.80 (2H).

Preparation of Intermediate 1.84-{2-[3-({6-Chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)propoxy]-4-fluorophenyl}-5-fluoropyridin-2-amine

A solution of diisopropyl azodicarboxylate (1.70 mL; 8.64 mmol) in THF(6.8 mL) was added dropwise to a mixture of3-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)propan-1-ol(1.96 g; 7.89 mmol, see Intermediate 1.4),2-(2-amino-5-fluoropyridin-4-yl)-5-fluorophenol (1.92 g; 8.64 mmol) andtriphenylphosphine (2.27 g; 8.64 mmol) in THF (34.0 mL) and the batchwas stirred at room temperature for 5 hours. Additionaltriphenylphosphine (1.04 g; 3.94 mmol) and diisopropyl azodicarboxylate(0.78 mL; 3.95 mmol) were added and the mixture was stirred at roomtemperature overnight. Additional diisopropyl azodicarboxylate (0.78 mL;3.95 mmol) was added and the mixture was stirred at room temperature for3 hours. Finally, additional triphenylphosphine (2.07 g; 7.89 mmol) anddiisopropyl azodicarboxylate (1.55 mL; 7.89 mmol) were added and themixture was stirred at room temperature for 3 hours before it wasconcentrated. The residue was by column chromatography on silica gel(hexane to hexane/ethyl acetate 75%) to give the desired title compound(2.37 g; 5.24 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=7.98 (1H), 7.25 (1H), 6.92 (1H), 6.76(2H), 6.59 (1H), 6.51 (1H), 4.41 (4H), 4.16 (2H), 3.56 (2H), 2.21 (2H),2.04 (3H).

Preparation of Intermediate 1.915,19-Difluoro-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine

A mixture of4-{2-[3-({6-chloro-4-[(methylsulfanyl)methyl]pyridin-2-yl}oxy)propoxy]-4-fluorophenyl}-5-fluoropyridin-2-amine(300 mg; 0.66 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (55 mg; 0.07 mmol; ABCR GmbH & CO. KG) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (32 mg; 0.07mmol; Aldrich Chemical Company Inc.) and potassium phosphate (705 mg;3.32 mmol) in toluene (50 ml) and NMP (6 mL) was stirred under anatmosphere of argon at 110° C. in a closed vessel for 150 minutes. Aftercooling, the batch was diluted with DCM and ethyl acetate and washedwith aqueous sodium chloride solution. The organic layer was filteredusing a Whatman filter and concentrated. The residue was purified bycolumn chromatography on silica gel (hexane to hexane/ethyl acetate 50%)to give the desired product (192 mg; 0.46 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.81 (1H), 8.18 (1H), 7.63 (1H), 7.11(1H), 6.79 (1H), 6.72 (1H), 6.23 (2H), 4.63 (2H), 4.07 (2H), 3.55 (2H),2.29 (2H), 2.06 (3H).

Preparation of Intermediate 1.10(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate

To ethyl o-(mesitylenesulfonyl)acetohydroxamate (69 mg; 0.24 mmol;Aldrich Chemical Company Inc.) in dioxane (0.25 ml) was added perchloricacid (70%; 0.25 ml) dropwise at 0° C. After additional vigorous stirringfor 10 minutes at 0° C., some cold water was added and the product MSH(O-(mesitylenesulfonyl) hydroxylamine) was extracted three times withDCM. The combined organic layers were washed with brine and dried oversodium sulfate. This solution of MSH in DCM was slowly added to asolution of15,19-difluoro-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine(100 mg; 0.24 mmol) in DCM (0.25 ml) at 0° C. The reaction mixture wasstirred at RT for 16 hours. UPLC-MS analysis indicated about 50%conversion. Additional MSH in DCM was prepared according to thedescribed procedure using ethyl o-(mesitylenesulfonyl)acetohydroxamate(35 mg; 0.24 mmol) and added to the reaction mixture at 0° C. Thereaction mixture was stirred at RT overnight. The mixture was cooled to0° C. and the suspension was suction filtered. The solid was washed withDCM and dried in vacuo to give the desired title compound (117 mg; 0.19mmol).

¹H-NMR (400 MHz, DMSO-d6) δ=2.10 (2H), 2.17 (3H), 3.07 (3H), 4.09-4.16(2H), 4.29 (1H), 4.44-4.58 (3H), 6.02 (2H), 6.25 (1H), 6.58 (1H), 6.74(2H), 6.92 (1H), 7.10 (1H), 7.50-7.62 (1H), 8.36 (1H), 8.69 (1H), 9.96(1H).

Example 1—Preparation of End Product

In an oven dry flask, under an atmosphere of argon,(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (125 mg; 0.20 mmol) was dissolved in DMF(0.5 ml) and cooled to 0° C. Sodium carbonate (25 mg; 0.24 mmol) wasadded followed by N-chlorosuccinimide (32 mg, 0.24 mmol), and thereaction mixture was stirred for 15 min at 0° C. Hexamethyldisilazane(96 mg; 0.60 mmol) was added and the reaction mixture was stirred atroom temperature for 4 h. The mixture was diluted with ethyl acetate andTHF, washed with aqueous sodium chloride solution, filtered using aWhatman filter and concentrated. The residue was purified by preparativeHPLC (Autopurifier: basic conditions) to give the desired title compound(3.6 mg; 0.01 mmol).

¹H NMR (400 MHz, DMSO-d6, 300K) δ=2.10 (2H), 2.42-2.48 (2H), 2.87 (3H),4.09-4.16 (2H), 4.19 (2H), 4.45-4.56 (2H), 6.27 (1H), 6.59 (1H), 6.90(1H), 7.09 (1H), 7.58 (1H), 8.32 (1H), 8.70 (1H), 9.70 (1H).

Example 1—Alternative Preparation of End Product

In an oven dry flask, under an atmosphere of argon, hexamethyldisilazane(26 mg; 0.16 mmol) was added to a suspension of(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (50 mg; 0.08 mmol) in DCM (0.45 ml) at0° C. Sodium carbonate (9 mg; 0.09 mmol) was added and the reactionmixture was stirred for 15 min at 0° C. Iodobenzene diacetate (28 mg;0.09 mmol) was added and the reaction mixture was stirred at 0° C. for 4h before the mixture was stirred at RT overnight. The mixture wasdiluted with DCM, washed with aqueous sodium chloride solution, filteredusing a Whatman filter and concentrated. The residue was purified bypreparative HPLC to give the desired title compound (10 mg; 0.02 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: YMC Triart 5μ 100×30mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 19% B (25→70 mL/min), 0.51-5.50 min 38-58% B (70mL/min),

DAD scan: 210-400 nm

Example 2(rac)-3-(2-{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}-2-methyl-2λ⁶-diazathia-1,2-dien-1-yl)propan-1-ol

In an oven dry flask, under an atmosphere of argon, 3-aminopropan-1-ol(23 mg; 0.32 mmol) was added to a suspension of(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (100 mg; 0.16 mmol; see Intermediate1.10) in DCM (0.90 ml) at 0° C. Sodium carbonate (18 mg; 0.17 mmol) wasadded and the reaction mixture was stirred for 15 min at 0° C.Iodobenzene diacetate (56 mg; 0.17 mmol) was added and the reactionmixture was stirred at 0° C. for 4 h. The mixture was diluted with DCM,washed with aqueous sodium chloride solution, filtered using a Whatmanfilter and concentrated. The residue was purified by preparative HPLC togive the desired title compound (6 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.1 vol % formic acid (99%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 26% B (25→70 mL/min), 0.51-5.50 min 26-46% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=1.55 (2H), 2.09 (2H), 2.79 (3H),2.84-3.06 (2H), 3.45 (2H), 4.12 (2H), 4.16-4.31 (2H), 4.36-4.59 (2H),6.27 (1H), 6.57 (1H), 6.90 (1H), 7.05-7.12 (1H), 7.58 (1H), 8.32 (1H),8.70 (1H), 9.71 (1H).

Example 3(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(imino)methyl-λ⁶-sulfanylidene]cyanamide

In an oven dry flask, under an atmosphere of argon, sodium cyanoazanide(20 mg; 0.32 mmol) was added to a suspension of(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (100 mg; 0.16 mmol; see Intermediate1.10) in DCM (0.90 ml) at 0° C. Sodium carbonate (18 mg; 0.17 mmol) wasadded and the reaction mixture was stirred for 15 min at 0° C.Iodobenzene diacetate (56 mg; 0.17 mmol) was added and the reactionmixture was stirred at 0° C. for 4 h. The mixture was diluted with DCM,washed with aqueous sodium chloride solution, filtered using a Whatmanfilter and concentrated. The residue was purified by preparative HPLC togive the desired title compound (7 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.1 vol % formic acid (99%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 37% B (25→70 mL/min), 0.51-5.50 min 37-59% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=2.07 (2H), 3.23 (3H), 4.08-4.16 (2H),4.46-4.55 (3H), 4.65 (2H), 6.31 (1H), 6.63 (1H), 6.90 (1H), 7.09 (1H),7.58 (1H), 8.33 (1H), 8.68 (1H), 9.83 (1H).

Example 4(rac)-8-[(N,S-dimethylsulfonodiimidoyl)methyl]-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine

In an oven dry flask, under an atmosphere of argon, a 2M solution ofmethylamine (0.09 ml; 0.18 mmol) in THF was added to a suspension of(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (55 mg; 0.09 mmol; see Intermediate1.10) in DCM (0.50 ml) at 0° C. Sodium carbonate (10 mg; 0.10 mmol) wasadded and the reaction mixture was stirred for 15 min at 0° C.Iodobenzene diacetate (31 mg; 0.10 mmol) was added and the reactionmixture was stirred at 0° C. for 4 h. The mixture was diluted with DCM,washed with aqueous sodium chloride solution, filtered using a Whatmanfilter and concentrated. The residue was purified by preparative HPLC togive the desired title compound (2 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 36% B (25→70 mL/min), 0.51-5.50 min 36-56% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=2.09 (2H), 2.57-2.62 (3H), 2.77 (3H),4.12 (2H), 4.22 (2H), 4.50 (2H), 6.26 (1H), 6.57 (1H), 6.90 (1H), 7.08(1H), 7.58 (1H), 8.32 (1H), 8.70 (1H), 9.71 (1H).

Example 516,20-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

Preparation of Intermediate 5.1 3-(Chloromethyl)-5-nitrophenol

Thionyl chloride (84.0 g; 712 mmol) was added dropwise to a stirredsolution of 3-(hydroxymethyl)-5-nitrophenol (60.0 g; 355 mmol; CAS-No.180628-74-4 purchased from Struchem) in DMF (1200 mL) at 0° C. Themixture was stirred at 10° C. for 3 hours. The mixture was concentrated,diluted with water and extracted three times with ethyl acetate. Thecombined organic layers were washed twice with water and concentrated toafford the crude title compound (60.0 g, 320 mmol) that was used withoutfurther purification.

Preparation of Intermediate 5.2 3-[(Methylsulfanyl)methyl]-5-nitrophenol

To a solution of crude 3-(chloromethyl)-5-nitrophenol (60.0 g; 320 mmol)in acetone (600 mL) at room temperature was added an aqueous solution ofsodium thiomethoxide (21%, 180 mL). The mixture was stirred at roomtemperature for 3 hours before additional aqueous solution of sodiumthiomethoxide (21%, 180 mL) was added and the mixture was stirred atroom temperature overnight. Finally, additional aqueous solution ofsodium thiomethoxide (21%, 90 mL) was added and the mixture was stirredat room temperature for 6 hours. The batch was diluted with ethylacetate and an aqueous solution of sodium chloride and extracted threetimes with ethyl acetate. The combined organic layers were concentratedand the residue was purified by column chromatography on silica gel(pentane/ethyl acetate 4:1) to afford the desired title compound (60.0g, 302 mmol).

¹H NMR (300 MHz, CDCl₃, 300K) δ=7.71 (1H), 7.57 (1H), 7.15 (1H), 3.66(2H), 1.99 (3H).

Preparation of Intermediate 5.3 Ethyl4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate

Ethyl 4-bromobutanoate (15.8 g; 81 mmol) was added dropwise to a stirredmixture of 3-[(methylsulfanyl)methyl]-5-nitrophenol (15.0 g; 75 mmol)and potassium carbonate (12.5 g; 90 mmol) in DMF (150 mL) at 0° C. Themixture was stirred at room temperature overnight. The mixture wasdiluted with water and extracted three times with ethyl acetate. Thecombined organic layers were washed twice with water and concentrated toafford the crude title compound (17.6 g) that was used without furtherpurification.

¹H NMR (300 MHz, DMSO-d6, 300K) δ=7.74 (1H), 7.53 (1H), 7.30 (1H), 4.03(3H), 3.75 (2H), 3.50 (1H), 2.42 (3H), 1.99 (1H), 1.92 (3H), 1.14 (3H).

Preparation of Intermediate 5.44-{3-[(Methylsulfanyl)methyl]-5-nitrophenoxy}butan-1-ol

A solution of DIBAL in hexane (1N; 176 mL) was added dropwise to astirred solution of crude ethyl4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butanoate (17.6 g) in dryTHF (400 mL) at −25° C. The mixture was stirred at 0° C. for 150minutes. Water (200 mL) was added dropwise, the mixture was acidifiedwith an aqueous solution of hydrogen choride (1N) to pH 4-5 andextracted three times with ethyl acetate. The combined organic layerswere concentrated and the residue was purified by column chromatographyon silica gel (pentane/ethyl acetate=4:1 to 2:1) to afford the desiredtitle compound (14.0 g, 51.7 mmol).

¹H NMR (300 MHz, DMSO-d6, 300K) δ=7.71 (1H), 7.50 (1H), 7.28 (1H), 4.43(1H), 4.03 (2H), 3.73 (2H), 3.43 (2H), 1.92 (3H), 1.74 (2H), 1.54 (2H).

Preparation of Intermediate 5.52-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine

A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; AldrichChemical Company Inc.), (4-fluoro-2-methoxyphenyl)boronic acid (224 mg;1.31 mmol; Aldrich Chemical Company Inc.) andtetrakis(triphenylphosphin)palladium(0) (138 mg; 0.12 mmol) in1,2-dimethoxyethane (3.6 ml) and an aqueous 2M solution of potassiumcarbonate (1.8 ml) was degassed using argon. The batch was stirred underan atmosphere of argon for 16 hours at 90° C. After cooling the batchwas diluted with ethyl acetate and washed with saturated aqueous sodiumchloride solution. The organic layer was filtered using a Whatman filterand concentrated. The residue was purified by column chromatography(hexane/ethyl acetate 1:1) to give the desired title compound (106 mg;0.41 mmol).

¹H NMR (400 MHz, CDCl₃, 300K) δ=8.47 (1H), 7.51 (1H), 6.82 (1H), 6.73(1H), 3.85 (3H).

Preparation of Intermediate 5.62-(2-Chloro-5-fluoropyrimidin-4-yl)-5-fluorophenol

A solution of boron tribromide in DCM (1M; 43.3 mL; 47.1 mmol; AldrichChemical Company Inc.) was added dropwise to a stirred solution of2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (2.00 g; 7.79mmol) in DCM (189 mL) at 0° C. The mixture was slowly warmed to roomtemperature while stirring overnight. The mixture was cautiously dilutedwith an aqueous solution of sodium bicarbonate under stirring at 0° C.and stirred at room temperature for 1 hour. Solid sodium chloride wasadded and the mixture filtered using a Whatman filter. The organic layerwas concentrated to give the crude title compound (1.85 g) that was usedwithout further purification.

¹H NMR (400 MHz, DMSO-d6, 300K) δ=10.80 (1H), 8.90 (1H), 7.50 (1H), 6.83(1H), 6.78 (1H).

Preparation of Intermediate 5.72-Chloro-5-fluoro-4-[4-fluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]pyrimidine

A solution of diisopropyl azodicarboxylate (0.41 mL; 2.06 mmol) in THF(1.6 mL) was added dropwise to a mixture of4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butan-1-ol (511 mg; 1.88mmol; see Intermediate 5.4),2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenol (500 mg; 2.06 mmol)and triphenylphosphine (541 mg; 2.06 mmol) in THF (8.1 mL) and the batchwas stirred at room temperature overnight. The mixture was concentratedand the residue was purified by column chromatography on silica gel(hexane to hexane/ethyl acetate 50%) to give the desired title compound(579 mg; 1.11 mmol).

¹H NMR (400 MHz, DMSO-d6, 300K) δ=8.87 (1H), 7.77 (1H), 7.54 (2H), 7.31(1H), 7.16 (1H), 6.97 (1H), 4.14 (2H), 4.08 (2H), 3.78 (2H), 1.95 (3H),1.79 (4H).

Preparation of Intermediate 5.83-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,208 mg) was added to a solution of2-chloro-5-fluoro-4-[4-fluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]pyrimidine(1060 mg; 2.14 mmol) in methanol (30 mL) and THF (10 mL) and the mixturewas stirred for 4 hours at room temperature under a hydrogen atmosphere.The mixture was filtered and the filtrate was concentrated to give thecrude title compound (851 mg) that was used without furtherpurification.

¹H NMR (400 MHz, DMSO-d6, 300K) δ=1.65-1.79 (4H), 1.92 (3H), 3.44 (2H),3.82 (2H), 4.10 (2H), 5.02 (2H) 5.97 (2H), 6.07 (1H), 6.95 (1H), 7.15(1H), 7.52 (1H), 8.88 (1H).

Preparation of Intermediate 5.916,20-difluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

A mixture of crude3-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline(760 mg),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (135 mg; 0.16 mmol; ABCR GmbH & CO. KG)and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (78 mg; 0.16mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1731 mg;8.16 mmol) in toluene (125 ml) and NMP (15 mL) was stirred under anatmosphere of argon at 110° C. for 3 hours. After cooling, additionalchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (135 mg; 0.16 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (78 mg; 0.16mmol) was added and the mixture was stirred for 6 hours at 110° C. Aftercooling, additionalchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (68 mg; 0.08 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (39 mg; 0.08mmol) was added and the mixuture was stirred for 3 hours at 110° C.After cooling, the batch was diluted with ethyl acetate and washed withaqueous sodium chloride solution. The organic layer was filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 50%) togive the desired title compound (207 mg; 0.48 mmol).

1H-NMR (400 MHz, DMSO-d6): δ=1.78-1.91 (4H), 1.96 (3H), 3.55 (2H),4.05-4.16 (2H), 4.26 (2H), 6.36 (1H), 6.59 (1H), 6.87 (1H), 7.10-7.18(1H), 7.39 (1H), 7.86 (1H), 8.65 (1H), 9.70 (1H).

Preparation of Intermediate 5.10(rae)-[{[16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate

To ethyl o-(mesitylenesulfonyl)acetohydroxamate (33 mg; 0.12 mmol;Aldrich Chemical Company Inc.) in dioxane (0.12 ml) was added perchloricacid (70%; 0.12 ml) dropwise at 0° C. After additional vigorous stirringfor 10 minutes at 0° C., some cold water was added and the product MSH(O-(mesitylenesulfonyl)hydroxylamine) was extracted three times withDCM. The combined organic layers were washed with brine and dried oversodium sulfate. This solution of MSH in DCM was slowly added to asolution of16,20-difluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine(50 mg; 0.12 mmol) in DCM (0.12 ml) at 0° C. The reaction mixture wasstirred at RT for 22 hours. UPLC-MS analysis indicated about 60%conversion. Additional MSH in DCM was prepared according to thedescribed procedure using ethyl o-(mesitylenesulfonyl)acetohydroxamate(17 mg; 0.06 mmol) and added to the reaction mixture at 0° C. Thereaction mixture was stirred at RT overnight. The mixture was cooled to0° C. for 3 hours and the suspension was suction filtered. The solid waswashed with DCM and dried in vacuo to give the desired title compound(60 mg; 0.09 mmol).

¹H-NMR (400 MHz, DMSO-d6) δ=1.86 (4H), 2.16 (3H), 3.01 (3H), 4.14 (2H),4.28 (3H), 4.49 (1H), 5.93 (2H), 6.50 (1H), 6.68 (1H), 6.74 (2H), 6.89(1H), 7.16 (1H), 7.39 (1H), 8.02 (1H), 8.69 (1H), 9.94 (1H).

Example 5—Preparation of End Product

In an oven dry flask, under an atmosphere of argon, hexamethyldisilazane(29 mg; 0.18 mmol) was added to a suspension of(rac)-[{[16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (58 mg; 0.09 mmol) in DCM (0.50 ml) at0° C. Sodium carbonate (10 mg; 0.10 mmol) was added and the reactionmixture was stirred for 15 min at 0° C. Iodobenzene diacetate (32 mg;0.10 mmol) was added and the reaction mixture was stirred at 0° C. for 4h before the mixture was stirred at RT overnight. The mixture wasdiluted with DCM, washed with aqueous sodium chloride solution, filteredusing a Whatman filter and concentrated. The residue was purified bypreparative HPLC to give the desired title compound (21 mg; 0.04 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 28% B (25→70 mL/min), 0.51-5.50 min 56-76% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=1.86 (4H), 2.78 (3H), 4.13 (s, 4H),4.27 (2H), 6.49-6.51 (1H), 6.67 (1H), 6.87 (1H), 7.14 (1H), 7.38 (1H),7.93 (1H), 8.65 (1H), 9.75 (1H).

Example 616,20,21-trifluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

Preparation of Intermediate 6.12-chloro-4-(3,4-difluoro-2-methoxyphenyl)-5-fluoropyrimidine

A batch with 2,4-dichloro-5-fluoropyrimidine (4.04 g; 24.2 mmol; AldrichChemical Company Inc.), (3,4-fluoro-2-methoxyphenyl)boronic acid (5.00g; 26.6 mmol; AOBChem USA) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1.96 g; 2.4 mmol) in 1,2-dimethoxyethane (65 ml) and anaqueous 2M solution of potassium carbonate (36 ml) was degassed usingargon. The batch was stirred under an atmosphere of argon for 3 hours at90° C. After cooling the batch was diluted with ethyl acetate and washedwith saturated aqueous sodium chloride solution. The organic layer wasfiltered using a Whatman filter and concentrated. The residue waspurified by column chromatography (DCM to DCM/EtOH 50%) to give thedesired title compound (5.1 g; 18.4 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.95 (d, 3H), 7.34-7.43 (m, 2H), 9.01(d, 1H).

Preparation of Intermediate 6.26-(2-chloro-5-fluoropyrimidin-4-yl)-2,3-difluorophenol

A solution of boron tribromide in DCM (1M; 5.1 mL; 5.1 mmol; AldrichChemical Company Inc.) was added dropwise to a stirred solution of2-chloro-4-(3,4-difluoro-2-methoxyphenyl)-5-fluoropyrimidine (250 mg;0.9 mmol) in DCM (26 mL) at 0° C. The mixture was slowly warmed to roomtemperature while stirring overnight. The mixture was cautiously dilutedwith an aqueous solution of sodium bicarbonate under stirring at 0° C.and stirred at room temperature for 1 hour. A saturated aqueous sodiumchloride solution was added and the mixture was diluted with ethylacetate. The mixture was filtered using a Whatman filter andconcentrated to give the crude title compound (196 mg) that was usedwithout further purification.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.02-7.10 (m, 1H), 7.27-7.41 (m, 1H),8.96 (d, 1H), 11.09 (br s, 1H).

Preparation of Intermediate 6.32-chloro-4-[3,4-difluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]-5-fluoropyrimidine

A solution of diisopropyl azodicarboxylate (0.83 mL; 4.20 mmol) in DCM(3.0 mL) was added dropwise to a mixture of4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butan-1-ol (1.14 g; 4.20mmol; see Intermediate 5.4),6-(2-chloro-5-fluoropyrimidin-4-yl)-2,3-difluorophenol (1.00 g; 3.84mmol) and triphenylphosphine (1.10 g; 4.20 mmol) in DCM (8.0 mL) at 0°C. and the batch was stirred at room temperature overnight.Triphenylphosphine (1.00 g; 3.84 mmol) and a solution of diisopropylazodicarboxylate (0.76 mL; 3.84 mmol) in DCM (3.0 mL) was added at roomtemperature and the mixture was stirred for additional 16 hours. Themixture was diluted with water and extracted three times with ethylacetate. The combined organic phase was filtered using a Whatman filterand concentrated. The residue was purified by column chromatography onsilica gel (hexane to hexane/ethyl acetate 50%) to give the desiredtitle compound (1.62 g; 3.15 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.62-1.81 (m, 4H), 1.96 (s, 3H), 3.79(s, 2H), 4.02 (t, 2H), 4.13-4.23 (m, 2H), 7.30-7.43 (m, 3H), 7.54 (t,1H), 7.78 (t, 1H), 8.99 (d, 1H).

Preparation of Intermediate 6.43-{4-[6-(2-chloro-5-fluoropyrimidin-4-yl)-2,3-difluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,200 mg) was added to a solution of2-chloro-4-[3,4-difluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]-5-fluoropyrimidine(815 mg; 1.59 mmol) in methanol (30 mL) and the mixture was stirred for1 hour at room temperature under a hydrogen atmosphere. Additionalplatinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,200 mg) was added and the mixture was stirred for 1 hour at roomtemperature under a hydrogen atmosphere. The mixture was filtered andthe filtrate was concentrated to give the crude title compound (793 mg)that was used without further purification.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.57-1.77 (m, 4H), 1.94 (s, 3H), 3.46(s, 2H), 3.78 (t, 2H), 4.17 (t, 2H), 5.04 (s, 2H), 5.95-6.00 (m, 2H),6.09 (t, 1H), 7.34-7.44 (m, 2H), 9.00 (d, 1H).

Preparation of Intermediate 6.516,20,21-trifluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

A mixture of crude3-{4-[6-(2-chloro-5-fluoropyrimidin-4-yl)-2,3-difluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline(500 mg),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (85 mg; 0.10 mmol; ABCR GmbH & CO. KG) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (49 mg; 0.10mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1097 mg;5.17 mmol) in toluene (77 ml) and NMP (9 mL) was stirred under anatmosphere of argon at 110° C. for 4 hours. After cooling, the batch wasdiluted with aqueous sodium chloride solution and extracted with ethylacetate/THF (1:1; 2×). The combined organic phase was filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 50%) togive the desired title compound (96 mg; 0.21 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ=1.76-1.92 (m, 4H), 1.96 (s, 3H), 3.55 (s,2H), 4.18-4.32 (m, 4H), 6.36 (t, 1H), 6.62 (s, 1H), 7.20-7.35 (m, 2H),8.01 (t, 1H), 8.70 (d, 1H), 9.78 (s, 1H).

Preparation of Intermediate 6.6(rac)-(methyl{[16,20,21-trifluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}-λ⁴-sulfanylidene)ammonium2,4,6-trimethylbenzenesulfonate

To ethyl o-(mesitylenesulfonyl)acetohydroxamate (32 mg; 0.11 mmol;Aldrich Chemical Company Inc.) in dioxane (0.11 ml) was added perchloricacid (70%; 0.11 ml) dropwise at 0° C. After additional vigorous stirringfor 10 minutes at 0° C., some cold water was added and the product MSH(O-(mesitylenesulfonyl)hydroxylamine) was extracted three times withDCM. The combined organic layers were washed with brine and dried oversodium sulfate. This solution of MSH in DCM was slowly added to asolution of16,20,21-trifluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine(50 mg; 0.11 mmol) in DCM (0.12 ml) at 0° C. The reaction mixture wasstirred at RT for 20 hours. The mixture was kept at 0° C. for 16 hours.Diethlyether (1 mL) was added and the mixture was kept overnight at 0°C. before the resulting suspension was suction filtered. The solid waswashed with diethylether and dried in vacuo to give the desired titlecompound (40 mg; 0.06 mmol).

¹H-NMR (400 MHz, DMSO-d6) δ=1.79-1.92 (m, 4H), 2.16 (s, 3H), 3.01 (s,3H), 4.23-4.33 (m, 5H), 4.49 (d, 1H), 5.90 (br s, 2H), 6.51 (s, 1H),6.69-6.74 (m, 3H), 7.22-7.29 (m, 1H), 7.31-7.39 (m, 1H), 8.17 (s, 1H),8.74 (d, 1H), 10.02 (s, 1H).

Example 6—Preparation of End Product

In an oven dry flask, under an atmosphere of argon, hexamethyldisilazane(19 mg; 0.12 mmol) was added to a suspension of (rac)-(methyl{[16,20,21-trifluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}-λ⁴-sulfanylidene)ammonium2,4,6-trimethylbenzenesulfonate 2,4,6-trimethylbenzenesulfonate (40 mg;0.06 mmol) in DCM (0.40 ml) at 0° C. Sodium carbonate (7 mg; 0.07 mmol)was added and the reaction mixture was stirred for 15 min at 0° C.Iodobenzene diacetate (21 mg; 0.05 mmol) was added and the reactionmixture was stirred at 0° C. for 4 h before the mixture was stirred atRT overnight. The mixture was diluted with DCM, washed with aqueoussodium chloride solution, filtered using a Whatman filter andconcentrated. The residue was purified by preparative HPLC to give thedesired title compound (8 mg; 0.02 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 28% B (25→70 mL/min), 0.51-5.50 min 56-76% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=1.73-1.98 (m, 4H), 2.25-2.37 (m, 2H),2.79 (s, 3H), 4.14 (s, 2H), 4.21-4.31 (m, 4H), 6.49-6.52 (m, 1H), 6.70(s, 1H), 7.20-7.35 (m, 2H), 8.08 (t, 1H), 8.70 (d, 1H), 9.82 (s, 1H).

Example 716,21-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecinee

Preparation of Intermediate 7.12-chloro-5-fluoro-4-(3-fluoror-2-methoxyphenyl)pyrimidine

A batch with 2,4-dichloro-5-fluoropyrimidine (4.96 g; 29.7 mmol; AldrichChemical Company Inc.),(3-fluoro-1-fluoro-4-(3-fluoro-2-methoxyphenyl)pyrimidnic acid (5.56 g;32.7 mmol ABCR GmbH & O. KG) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (2.43 g; 2.9 mmol) in 1,2-dimethoxyethane (80 ml) and anaqueous 2M solution of potassium carbonate (45 ml) was degassed usingargon. The batch was stirred under an atmosphere of argon for 3 hours at90° C. After cooling the batch was diluted with ethyl acetate and washedwith saturated aqueous sodium chloride solution. The organic layer wasfiltered using a Whatman filter and concentrated. The residue waspurified by column chromatography (DCM to DCM/EtOH 50%) to give thedesired title compound (6.7 g; 26.0 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.87 (d, 3H), 7.26-7.37 (m, 2H), 7.55(ddd, 1H), 9.01 (d, 1H1).

Preparation of Intermediate 7.22-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluorophenol

A solution of boron tribromide in DCM (1M; 65.0 mL; 65.0 mmol; AldrichChemical Company Inc.) was added dropwise to a stirred solution of2-chloro-5-fluoro-4-(3-fluoro-2-methoxyphenyl)pyrimidine (3.0 g; 11.69mmol) in DCM (312 mL) at 0° C. The mixture was slowly warmed to roomtemperature while stirring overnight. The mixture was cautiously dilutedwith an aqueous solution of sodium bicarbonate under stirring at 0° C.and stirred at room temperature for 1 hour before it was extracted threetimes with DCM. The combined organic phase was filtered using a Whatmanfilter and concentrated to give the crude title compound (2.8 g) thatwas used without further purification.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=6.99 (td, 1H), 7.26 (dt, 1H), 7.41(ddd, 1H), 8.96 (d, 1H), 10.45 (s, 1H).

Preparation of Intermediate 7.32-chloro-5-fluoro-4-[3-fluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]pyrimidine

A solution of diisopropyl azodicarboxylate (0.89 mL; 4.51 mmol) in DCM(3.0 mL) was added dropwise to a mixture of4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butan-1-ol (1.23 g; 4.51mmol; see Intermediate 5.4),2-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluorophenol (1.00 g; 4.12 mmol)and triphenylphosphine (1.18 g; 4.51 mmol) in DCM (8.0 mL) at 0° C. andthe batch was stirred at room temperature overnight. Another portion oftriphenylphosphine (1.08 g; 4.12 mmol), and a solution of diisopropylazodicarboxylate (0.81 mL; 4.12 mmol) in DCM (3.0 mL) were added at roomtemperature and the mixture was stirred for additional 16 hours. Themixture was concentrated and the residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 50%) togive the desired title compound (2.00 g), still containing someimpurities.

Preparation of Intermediate 7.43-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline

Platinum 1% and vanadium 2%, on activated carbon (50-70% wetted powder,200 mg) was added to a solution of2-chloro-5-fluoro-4-[3-fluoro-2-(4-{3-[(methylsulfanyl)methyl]-5-nitrophenoxy}butoxy)phenyl]pyrimidine(1.04 g) in methanol (30 mL) and the mixture was stirred for 80 minutesat room temperature under a hydrogen atmosphere. Additional platinum 1%and vanadium 2%, on activated carbon (50-70% wetted powder, 200 mg) wasadded and the mixture was stirred for 2 hours at room temperature undera hydrogen atmosphere. The mixture was filtered and the filtrate wasconcentrated to give the crude title compound (951 mg) that was usedwithout further purification.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.55-1.80 (m, 4H), 1.94 (s, 3H),3.41-3.51 (m, 2H), 3.77 (t, 2H), 4.00-4.13 (m, 2H), 5.04 (br s, 2H),5.95-6.00 (m, 2H), 6.09 (t, 1H), 7.26-7.37 (m, 2H), 7.54 (ddd, 1H), 9.00(d, 1H).

Preparation of Intermediate 7.516,21-difluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

A mixture of crude3-{4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluorophenoxy]butoxy}-5-[(methylsulfanyl)methyl]aniline(510 mg),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tert-butylether adduct (91 mg; 0.11 mmol; ABCR GmbH & CO. KG) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (52 mg; 0.11mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1162 mg;5.47 mmol) in toluene (81 ml) and NMP (10 mL) was stirred under anatmosphere of argon at 110° C. overnight. After cooling, the batch wasdiluted with aqueous sodium chloride solution and extracted twice withethyl acetate/THF (1:1). The combined organic phase was filtered using aWhatman filter and concentrated. The residue was purified by columnchromatography on silica gel (hexane to hexane/ethyl acetate 50%) togive the desired title compound (171 mg; 0.40 mmol).

¹H-NMR (400 MHz, DMSO-d6): δ=1.79 (br s, 2H), 1.86 (br d, 2H), 1.96 (s,3H), 3.55 (s, 2H), 4.18 (br s, 2H), 4.21-4.28 (m, 2H), 6.36 (s, 1H),6.62 (s, 1H), 7.17 (dt, 1H), 7.26-7.32 (m, 1H), 7.45 (ddd, 1H), 8.03 (s,1H), 8.70 (d, 1H), 9.76 (s, 1H).

Preparation of Intermediate 7.6(rac)-[{[16,21-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate

To ethyl o-(mesitylenesulfonyl)acetohydroxamate (80 mg; 0.28 mmol;Aldrich Chemical Company Inc.) in dioxane (0.28 ml) was added perchloricacid (70%; 0.28 ml) dropwise at 0° C. After additional vigorous stirringfor 10 minutes at 0° C., some cold water was added and the product MSH(O-(mesitylenesulfonyl)hydroxylamine) was extracted three times withDCM. The combined organic layers were washed with brine and dried oversodium sulfate. This solution of MSH in DCM was slowly added to asolution of16,21-difluoro-9-[(methylsulfanyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine(120 mg; 0.28 mmol) in DCM (0.28 ml) at 0° C. The reaction mixture wasstirred at RT overnight. The mixture was kept at 0° C. for 16 hours.Diethylether (1 mL) was added and the mixture was kept overnight at 0°C., before the resulting suspension was suction filtered. The solid waswashed with diethylether and dried in vacuo to give the desired titlecompound (64 mg; 0.10 mmol).

¹H-NMR (400 MHz, DMSO-d6) δ=1.76-1.91 (m, 4H), 2.17 (s, 3H), 3.01 (s,3H), 4.15-4.33 (m, 5H), 4.49 (d, 1H), 5.94 (s, 2H), 6.50 (s, 1H),6.69-6.75 (m, 3H), 7.13-7.23 (m, 1H), 7.25-7.36 (m, 1H), 7.42-7.51 (m,1H), 8.21 (s, 1H), 8.74 (d, 1H), 10.01 (s, 1H).

Example 7—Preparation of End Product

In an oven dry flask, under an atmosphere of argon, hexamethyldisilazane(32 mg; 0.20 mmol) was added to a suspension of(rac)-[{[16,21-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (64 mg; 0.10 mmol) in DCM (0.60 ml) at0° C. Sodium carbonate (12 mg; 0.11 mmol) was added and the reactionmixture was stirred for 15 min at 0° C. Iodobenzene diacetate (35 mg;0.11 mmol) was added and the reaction mixture was stirred at 0° C. for 4h before the mixture was stirred at RT overnight. The mixture wasdiluted with DCM, washed with aqueous sodium chloride solution, filteredusing a Whatman filter and concentrated. The residue was purified bypreparative HPLC to give the desired title compound (6 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 28% B (25→70 mL/min), 0.51-5.50 min 56-76% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=1.76-1.93 (m, 4H), 2.26-2.33 (m, 2H),2.79 (s, 3H), 4.11-4.29 (m, 6H), 6.50 (s, 1H), 6.70 (s, 1H), 7.16 (td,1H), 7.25-7.30 (m, 1H), 7.45 (ddd, 1H), 8.09-8.13 (m, 1H), 8.70 (d, 1H),9.81 (s, 1H).

Example 815,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7-carbonitrile

Preparation of Intermediate 8.115,19-difluoro-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7-carbonitrile

N-Iodosuccinimide (94 mg; 0.42 mmol) was added to a solution of15,19-difluoro-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine(145 mg; 0.35 mmol; see Intermediate 1.9) in DMF (1.0 mL) at roomtemperature. The reaction mixture was stirred for 2 hours, before it wasdiluted with DCM and washed with water. The organic phase wasconcentrated to give the crude product15,19-difluoro-7-iodo-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine.The crude product was re-dissolved in DMSO (2.0 ml), copper(I) cyanide(37 mg; 0.42 mmol) was added and the reaction mixture was stirred at140° C. for 1 hour. After cooling the reaction mixture was purified bypreparative HPLC to give the desired title compound (70 mg; 0.15 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.1 vol % formic acid (99%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 26% B (25→70 mL/min), 0.51-5.50 min 26-46% B (70mL/min), DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=2.06-2.18 (m, 5H), 3.68 (s, 2H),4.09-4.16 (m, 2H), 4.58-4.68 (m, 2H), 6.66 (s, 1H), 6.91 (td, 1H), 7.10(dd, 1H), 7.59 (ddd, 1H), 8.40 (d, 1H), 8.63 (d, 1H), 10.37 (s, 1H).

Preparation of Intermediate 8.2(rac)-[{[7-cyano-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate

To ethyl o-(mesitylenesulfonyl)acetohydroxamate (32 mg; 0.11 mmol;Aldrich Chemical Company Inc.) in dioxane (0.12 ml) was added perchloricacid (70%; 0.12 ml) dropwise at 0° C. After additional vigorous stirringfor 10 minutes at 0° C., some cold water was added and the product MSH(O-(mesitylenesulfonyl)hydroxylamine) was extracted three times withDCM. The combined organic layers were washed with brine and dried oversodium sulfate. This solution of MSH in DCM was slowly added to asuspension of15,19-difluoro-8-[(methylsulfanyl)methyl]-3,4-dihydro-2H,1H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7-carbonitrile(50 mg; 0.11 mmol) in DCM (0.11 ml) at 0° C. The reaction mixture wasstirred at RT overnight. The mixture was kept at 0° C. for 16 hours. Themixture was kept overnight at 0° C., before the resulting suspension wassuction filtered. The solid was washed with DCM and dried in vacuo togive the desired title compound (66 mg; 0.10 mmol). ¹H-NMR (400 MHz,DMSO-d6) δ=2.11-2.21 (m, 5H), 3.17 (s, 3H), 4.11-4.17 (m, 2H), 4.49 (d,1H), 4.62-4.71 (m, 3H), 6.14 (s, 2H), 6.74 (d, 3H), 6.93 (td, 1H),7.07-7.15 (m, 1H), 7.61 (ddd, 1H), 8.46 (d, 1H), 8.61 (d, 1H), 10.70 (s,1H).

Example 8—Preparation of End Product

In an oven dry flask, under an atmosphere of argon, hexamethyldisilazane(31 mg; 0.19 mmol) was added to a suspension of(rac)-[{[7-cyano-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(methyl)-4-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (63 mg; 0.10 mmol) in DCM (0.50 ml) at0° C. Sodium carbonate (11 mg; 0.11 mmol) was added and the reactionmixture was stirred for 15 min at 0° C. Iodobenzene diacetate (34 mg;0.11 mmol) was added and the reaction mixture was stirred at 0° C. for 4h before the mixture was stirred at RT ovemight. The mixture was dilutedwith DCM, washed with aqueous sodium chloride solution, filtered using aWhatman filter and concentrated. The residue was purified by preparativeHPLC to give the desired title compound (3 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 28% B (25→70 mL/min), 0.51-5.50 min 56-76% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=2.12 (br d, 2H), 2.96 (s, 3H),4.05-4.18 (m, 2H), 4.36 (s, 2H), 4.56-4.67 (m, 2H), 6.78 (s, 1H),6.85-6.94 (m, 1H), 7.08 (br d, 1H), 7.11 (br d, 1H), 7.59 (ddd, 1H),8.40 (d, 1H), 8.60 (d, 1H), 10.42 (s, 1H).

Example 9(rac)-9-[(N-cyclopropyl-S-methylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

In an oven dry flask, under an atmosphere of argon, sodium carbonate (17mg; 0.16 mmol) and N-chlorosuccinimide (21 mg; 0.16 mmol) was added to(rac)-[{[16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-2-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (84 mg; 0.13 mmol; see Intermediate5.10) in DMF (1.2 ml) at 0° C. and the mixture was stirred for 15 minbei 0° C. Cyclopropanamine (22 mg; 0.39 mmol) was added and the reactionmixture was stirred at RT overnight. The mixture was diluted withaqueous sodium chloride solution and extracted three times with DCM. Thecombined organic layer was filtered using a Whatman filter andconcentrated. The residue was purified by preparative HPLC to give thedesired title compound (6 mg; 0.01 mmol).

Preparative HPLC:

Instrument: Waters Autopurificationsystem; Column: Waters XBrigde C18 5μ100×30 mm;

Eluent A: H₂O+0.2 vol % aqueous NH₃ (32%), Eluent B: MeCN;

Gradient: 0.00-0.50 min 28% B (25→70 mL/min), 0.51-5.50 min 56-76% B (70mL/min),

DAD scan: 210-400 nm

¹H NMR (400 MHz, DMSO-d6, 300K) δ=0.22-0.44 (m, 4H), 1.86 (br s, 4H),2.09 (s, 1H), 2.42-2.48 (m, 1H), 2.72 (s, 3H), 4.09-4.24 (m, 4H), 4.27(br s, 2H), 6.51 (s, 1H), 6.68 (s, 1H), 6.87 (td, 1H), 7.15 (dd, 1H),7.35-7.42 (m, 1H), 7.94 (s, 1H), 8.66 (d, 1H), 9.77 (s, 1H).

Example 10(rac)-9-[(N,S-dimethylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine

In an oven dry flask, under an atmosphere of argon, a solution ofmethylamine in THF (2M, 0.16 mL; 0.31 mmol) was added to a suspension of(rac)-[{[16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecin-9-yl]methyl}(methyl)-λ⁴-sulfanylidene]ammonium2,4,6-trimethylbenzenesulfonate (see Intermediate 5.10; 100 mg; 0.16mmol) in DCM (0.90 ml) at 0° C. Sodium carbonate (18 mg; 0.17 mmol) wasadded and the reaction mixture was stirred for 15 min at 0° C.Iodobenzene diacetate (55 mg; 0.17 mmol) was added and the reactionmixture was stirred at 0° C. for 4 h before the mixture was stirred atRT overnight. The mixture was diluted with DCM, washed with aqueoussodium chloride solution, filtered using a Whatman filter andconcentrated. The residue was purified by preparative HPLC(Autopurifier: acidic conditions) to give the desired title compound (9mg; 0.02 mmol).

1H-NMR (500 MHz, DMSO-d6): Shift [ppm]=1.84-1.92 (m, 4H), 2.55 (s, 3H),2.69 (s, 3H), 4.10-4.15 (m, 2H), 4.17 (s, 2H), 4.26-4.29 (m, 2H), 6.48(s, 1H), 6.66 (s, 1H), 6.87 (td, 1H), 7.15 (dd, 1H), 7.38 (ddd, 1H),7.94 (s, 1H), 8.65 (d, 1H), 9.76 (s, 1H).

The following Table 1 provides an overview on the compounds described inthe example section:

TABLE 1 Example No. Structure Name of compound  1

15,19-difluoro-8-[(S- methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16- (metheno)-1,5,11,13-benzodioxadiazacyclooctadecine  2

(rac)-3-(2-{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}-2-methyl-2λ⁶-diazathia-1,2- dien-1-yl)propan-1-ol  3

(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin- 8-yl]methyl}(imino)methyl-λ⁶-sulfanylidene]cyanamide  4

(rac)-8-[(N,S- dimethylsulfonodiimidoyl)methyl]-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)- 12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine  5

16,20-difluoro-9-[(S- methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14-benzodioxadiazacyclononadecine  6

16,20,21-trifluoro-9-[(S- methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14-benzodioxadiazacyclononadecine  7

16,21-difluoro-9-[(S- methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7- (metheno)-1,6,12,14-benzodioxadiazacyclononadecine  8

15,19-difluoro-8-[(S- methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16- (metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7- carbonitrile  9

(rac)-9-[(N-cyclopropyl-S- methylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17- (azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine 10

(rac)-9-[(N,S- dimethylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17- (azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecineResults:

Table 2: Inhibition for CDK9 and CDK2 of compounds according to thepresent invention

The IC₅₀ (inhibitory concentration at 50% of maximal effect) values areindicated in nM, “n.t.” means that the compounds have not been tested inthe respective assay.

-   {circle around (1)}: Example Number-   {circle around (2)}: CDK9: CDK9/CycT1 kinase assay as described    under Method 1a. of Materials and Methods-   {circle around (3)}: CDK2: CDK2/CycE kinase assay as described under    Method 2. of Materials and Methods-   {circle around (4)}: Selectivity CDK9 over CDK2: IC₅₀ (CDK2)/IC₅₀    (CDK9) according to Methods 1a. and 2a. of Materials and Methods-   {circle around (5)}: high ATP CDK9: CDK9/CycT1 kinase assay as    described under Method 1b. of Materials and Methods-   {circle around (6)}: high ATP CDK2: CDK2/CycE kinase assay as    described under Method 2b. of Materials and Methods-   {circle around (7)}: Selectivity high ATP CDK9 over high ATP CDK2:    IC₅₀ (high ATP CDK2)/IC₅₀ (high ATP CDK9) according to Methods 1b.    and 2b. of Materials and Methods

Noteworthily, in the CDK9 assays, as described supra in the Methods 1a.and 1b. of Materials and Methods, resolution power is limited by theenzyme concentrations, the lower limit for IC₅₀s is about 1-2 nM in theCDK9 high ATP assay and 2-4 nM in the CDK low ATP assays. For compoundsexhibiting IC₅₀s in this range the true affinity to CDK9 and thus theselectivity for CDK9 over CDK2 might be even higher, i.e. for thesecompounds the selectivity factors calculated in columns 4 and 7 of Table2, infra, are minimal values, they could be also higher.

TABLE 2 {circle around (1)} Structure {circle around (2)} {circle around(3)} {circle around (4)} {circle around (5)} {circle around (6)} {circlearound (7)}  1

3.3 16.4 5.0 2.0 140 70  2

2.9 22.5 7.8 2.0 246 123  3

2.9 6.0 2.1 1.7 62.4 36.7  4

9.2 37.3 4.1 3.7 620 168  5

3.4 92.6 27.2 2.1 1240 590  6

8.2 1430 174 5.9 12500 2118  7

5.6 1170 209 3.4 7520 2132  8

3.7 71.2 19.2 1.5 378 252  9

3.6 143 39.7 2.3 997 433 10

Tbd tbd — 3.4 1650 485

Tables 3a and 3b: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR,NCI—H460, DU145, Caco-2, B16F10, A2780 and MOLM-13 cells by compoundsaccording to the present invention, determined as described under Method3. of Materials and Methods. All ICso (inhibitory concentration at 50%of maximal effect) values are indicated in nM, “n.t.” means that thecompounds have not been tested in the respective assay.

-   {circle around (1)}: Example Number-   {circle around (2)}: Inhibition of HeLa cell proliferation-   {circle around (3)}: Inhibition of HeLa-MaTu-ADR cell proliferation-   {circle around (4)}: Inhibition of NCI—H460 cell proliferation-   {circle around (5)}: Inhibition of DU145 cell proliferation-   {circle around (6)}: Inhibition of Caco-2 cell proliferation-   {circle around (7)}: Inhibition of B16F10 cell proliferation-   {circle around (8)}: Inhibition of A2780 cell proliferation-   {circle around (9)}: Inhibition of MOLM-13 cell proliferation

TABLE 3a Indications represented by cell lines Cell line SourceIndication HeLa ATCC Human cervical tumour HeLa-MaTu-ADR EPO-GmbHMultidrug-resistant human Berlin cervical carcinoma NCI-H460 ATCC Humannon-small cell lung carcinoma DU 145 ATCC Hormone-independent humanprostate carcinoma Caco-2 ATCC Human colorectal carcinoma B16F10 ATCCMouse melanoma A2780 ECACC Human ovarian carcinoma MOLM-13 DSMZ Humanacute myeloid leukemia

TABLE 3b Inhibition of proliferation {circle around (1)} Structure{circle around (2)} {circle around (3)} {circle around (4)} {circlearound (5)} {circle around (6)} {circle around (7)} {circle around (8)}{circle around (9)}  1

2.8 7.8 10.4 9.1 16.4 14.3 4.0 2.8  2

10.2 n.d. 89.8 29.5 28.7 37.4 5.4 5.3  3

n.d n.d. n.d. n.d. n.d. n.d. 2.6 2.0  4

n.d. n.d. n.d. n.d. n.d. n.d. 11.7 4.7  5

25.8 n.d. 38.3 36.2 35.2 50.6 11.7 8.2  6

313 n.d. 369 360 325 683 123 113  7

332 n.d. 448 396 396 784 125 126  8

5.5 n.d. n.d 11.2 43.1 50.7 18.1 4.2  9

31.6 n.d. 56 118 47.8 92.2 31.3 22.2 10

Tbd Tbd tbd Tbd Tbdt Tbd 29 tbd

Table 4: Caco-2 permeation of compounds according to the presentinvention, determined as described under Method 5 of Materials andMethods.

{circle around (1)}: Example Number

{circle around (2)}: Concentration of test compound indicated in μM.

{circle around (3)}: P_(app) A-B (M_(ari)) indicated in [nm/s]

{circle around (4)}: P_(app) B-A (M_(ari)) indicated in [nm/s]

{circle around (5)}: Efflux ratio (Papp B-A/Papp A-B)

TABLE 4 {circle around (1)} Structure {circle around (2)} {circle around(3)} {circle around (4)} {circle around (5)} 1

2 62.4  89.2 1.4 2

2 9.9 229.3  23.2 5

2 48.2* 240.5* 5.0 6

2 46.4  222.7  4.8 *mean of two individual measurements

Table 5: Stability in rat hepatocytes and t_(1/2) in rats after ivdosing as determined by Method 6. and Method 7. as described inMaterials and Methods.

{circle around (1)}: Example Number

{circle around (2)}: The maximal calculated oral bioavailability (Fmax)based on stability data in rat Hepatocytes.

{circle around (3)} t_(1/2): terminal half-life (in h) from in vivostudy after i.v. bolus dosing to rats.

TABLE 5 {circle around (1)} Structure {circle around (2)} {circle around(3)}  1

76% 3.4  2

58% n.t.  5

93% 6.9 10

46%

Table 6a: Equilibrium dissociation constants K_(D) [l/s], dissociationrate constants k_(off) [1/s], and target resident times [min] asdetermined by Method 8. at 25° C. as described in Materials and Methods.Slight variations of experimental parameters are indicated by letters(A-G):

Parameters A: Described in Materials and Methods section 8.

Parameters B: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

Parameters C: Flow rate: 50 μl/min, Injection time: 60 s, Dissociationtime: 1200 s, Serial dilutions of compound (0.82 nM up to 200 nM)

Parameters D: Flow rate: 100 μl/min, Injection time: 80 s, Dissociationtime: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

Parameters E: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (0.78 nM up to 25 nM) andmeasured at 37° C.

Parameters F: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (1.56 nM up to 50 nM)

Parameters G: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (3.13 nM up to 100 nM)

{circle around (1)}: Example Number

{circle around (2)}: Equilibrium dissociation constant K_(D) [l/s]

{circle around (3)}: Dissociation rate constant k_(off) [1/s]

{circle around (4)}: Target resident time [min]

{circle around (5)}: Experimental parameters as specified above [A-G]

TABLE 6a {circle around (1)} Structure {circle around (2)} {circlearound (3)} {circle around (4)} {circle around (5)} 1

<5.0E-5 <2.50E-5 >333 >666 A B 2

<5.0E-5 <2.50E-5* >333 >666* C B 3

<2.5E-5* <5.0E-5 >666* >333 B C 4

2.37E-10 1.57E-9  4.96E-5 <2,50E-5 <2,50E-5  2.37E-4  336 >666 >666  70B B B D 5

3.00E-11 7.96E-11 4.87E-10 6.39E-10  8.15E-5  2.53E-5 <2,50E-5 <2,50E-5 3.38E-4  4.12E-4  204  659 >666 >666  49  40 F F F F C D 6

2.60E-9*  1.88E-3*  9* B 7

1.94E-9*  1.54E-3*  11* G 8

1.92E-10*  3.26E-4*  51* G 9

2.79E-10*  2.11E-4*  79* F *Represent arithmetic means of more than onevalue

Dissociation rate constants below of what is resolvable with therespective assay are reported using the “<”-symbol (e.g. <2.5 E-5 s⁻¹)

It is expected that that the prolonged residence time of macrocyclicCDK9 inhibitors according to the invention will result in a sustainedinhibitory effect on CDK9 signaling, ultimately contributing tosustained target engagement and anti-tumor efficacy.

Table 6b: Equilibrium dissociation constants K_(D) [1/s], dissociationrate constants k_(off) [1/s], and target resident times [min] asdetermined by Method 8. at 37° C. as described in Materials and Methods.Slight variations of experimental parameters are indicated by letters(A-G):

Parameters A: Described in Materials and Methods section 8.

Parameters B: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

Parameters C: Flow rate: 50 μl/min, Injection time: 60 s, Dissociationtime: 1200 s, Serial dilutions of compound (0.82 nM up to 200 nM)

Parameters D: Flow rate: 100 μl/min, Injection time: 80 s, Dissociationtime: 1200 s, Serial dilutions of compound (3.13 nM up to 100 nM)

Parameters E: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (0.78 nM up to 25 nM) andmeasured at 37° C.

Parameters F: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (1.56 nM up to 50 nM)

Parameters G: Flow rate: 100 μl/min, Injection time: 70 s, Dissociationtime: 1100 s, Serial dilutions of compound (3.13 nM up to 100 nM)

{circle around (1)}: Example Number

{circle around (2)}: Equilibrium dissociation constant K_(D) [1/s]

{circle around (3)}: Dissociation rate constant k_(off) [1/s]

{circle around (4)}: Target resident time [min]

{circle around (5)}: Experimental parameters as specified above [A-G]

TABLE 6b {circle around (1)} Structure {circle around (2)} {circlearound (3)} {circle around (4)} {circle around (5)}  1

1.86E-10 1.18E-10 4.81E-11  3.92E-4  1.99E-4  8.15E-5 <8.0E-5  43  84 204 >208 E E E E  2

2.83E-10 1.35E-10 6.30E-11 5.94E-11 5.88E-11  2.68E-4  2.34E-4  2.48E-4<8,0E-5 <8,0E-5  2,39E-4  1.20E-4 <8,0E-5 <8,0E-5  62  71  67 >208 >208 70  139 >208 >208 E E E E E E E E E  3

1.46E-10 7.77E-11 1.09E-10 2.53E-10 3.01E-10  1.06E-4  1.13E-4  1.77E-4 2.44E-4  3.08E-4 <8.0E-5 <8.0E-5  157  147  94  68  54 >208 >208 E E EE E E E  4

 5

4.51E-10*  8.09E-4*  21* E 10

5.15E-10*  8.33E-4*  20* E *Represent arithmetic means of more than onevalue

Dissociation rate constants below of what is resolvable with therespective assay are reported using the “<”-symbol (e.g. <8.0E-5 s⁻¹)

It is expected that that the prolonged residence time of macrocyclicCDK9 inhibitors according to the invention will result in a sustainedinhibitory effect on CDK9 signaling, ultimately contributing tosustained target engagement and anti-tumor efficacy.

Table 7: Thermodynamic solubility of compounds according to the presentinvention in water at pH 6.5 as determined by the equilibrium shakeflask methods described under Method 4a. and 4b. of Materials andMethods; “n.t.” means that the compounds have not been tested in therespective assay.

-   {circle around (1)}: Example Number-   {circle around (2)}: Aqueous Solubility pH 6.5 [mg/L], thermodynamic    from DMSO solution as described under Method 4a. of Materials and    Methods-   {circle around (3)}: Aqueous Solubility pH 6.5 [mg/L], thermodynamic    from powder as described under Method 4b. of Materials and Methods

TABLE 7 {circle around (1)} Structure of compound {circle around (2)}{circle around (3)}   5

78 58 6

14 n.t. 9

70 n.t.

The invention claimed is:
 1. A compound of formula (I)

wherein: L is a C₂-C₅-alkylene group, wherein said group is optionallysubstituted with (i) one substituent selected from the group consistingof hydroxy, C₃-C₄-cycloalkyl-, hydroxy-C₁-C₃-alkyl-, and —(CH₂)NR⁶R⁷,and/or (ii) one or two or three additional substituents, identically ordifferently, selected from the group consisting of a fluorine atom and aC₁-C₃-alkyl-group, with the proviso that a C₂-alkylene group is notsubstituted with a hydroxy group; X and Y are CH or N with the provisothat one of X and Y is CH and one of X and Y is N; R¹ is a groupselected from the group consisting of C₁-C₆-alkyl- andC₃-C₅-cycloalkyl-, wherein said group is optionally substituted with oneor two or three substituents, identically or differently, selected fromthe group consisting of hydroxy, cyano, halogen, C₁-C₃-alkyl-,fluoro-C₁-C₂-alkyl-, C₁-C₃-alkoxy-, C₁-C₂-fluoroalkoxy-, —NH₂,alkylamino-, dialkylamino-, cyclic amines, —OP(═O)(OH)₂, —C(═O)OH, and—C(═O)NH₂; R² is a group selected from the group consisting of ahydrogen atom, a fluorine atom, a chlorine atom, cyano, C₁-C₂-alkyl-,C₁-C₂-alkoxy-, and fluoro-C₁-C₂-alkyl-; R³ and R⁴ are independently agroup selected from the group consisting of a hydrogen atom, a fluorineatom, a chlorine atom, cyano, C₁-C₂-alkyl-, C₁-C₂-alkoxy-,fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-; R⁵ is a group selectedfrom the group consisting of a hydrogen atom, cyano, —C(═O)R⁸,—C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, andphenyl-, wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl- or phenyl-group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from the group consisting of halogen, hydroxy,cyano, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-,cyclic amines, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-; R⁶ and R⁷are independently a group selected from the group consisting of ahydrogen atom, C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl-, and benzyl-,wherein said C₁-C₆-alkyl-, C₃-C₅-cycloalkyl-, phenyl- or benzyl-group isoptionally substituted with one, two or three substituents, identicallyor differently, selected from the group consisting of halogen, hydroxy,C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, cyclicamines, fluoro-C₁-C₂-alkyl-, and C₁-C₂-fluoroalkoxy-; or R⁶ and R⁷ aretaken together with the nitrogen atom to which they are attached to forma cyclic amine; and R⁸ is a group selected from the group consisting ofC₁-C₆-alkyl-, fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl-, phenyl-, andbenzyl-, wherein said group is optionally substituted with one, two orthree substituents, identically or differently, selected from the groupconsisting of halogen, hydroxy, C₁-C₃-alkyl-, C₁-C₃-alkoxy-, —NH₂,alkylamino-, dialkylamino-, cyclic amines, fluoro-C₁-C₂-alkyl-, andC₁-C₂-fluoroalkoxy-, or an enantiomer, a diastereomer, apharmaceutically acceptable salt, or a solvate thereof, or apharmaceutically acceptable salt of said solvate.
 2. The compound offormula (I) according to claim 1, wherein: L is a C₂-C₅-alkylene group,wherein said group is optionally substituted with (i) one substituentselected from the group consisting of C₃-C₄-cycloalkyl- andhydroxymethyl-, and/or (ii) one or two additional substituents,identically or differently, selected from the group consisting ofC₁-C₂-alkyl-; X and Y are CH or N with the proviso that one of X and Yis CH and one of X and Y is N; R¹ is a group selected from the groupconsisting of C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-, wherein said group isoptionally substituted with one or two or three substituents,identically or differently, selected from the group consisting ofhydroxy, cyano, halogen, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂, and—C(═O)OH; R² is a group selected from the group consisting of a hydrogenatom, a fluorine atom, a chlorine atom, cyano, methyl-, methoxy-, andtrifluoromethyl-; R³ is a group selected from the group consisting of ahydrogen atom, a fluorine atom, a chlorine atom, cyano, methyl-,methoxy-, trifluoromethyl-, and trifluoromethoxy-; R⁴ is a hydrogen atomor a fluorine atom; R⁵ is a group selected from the group consisting ofa hydrogen atom, cyano, —C(═O)R⁸, —C(═O)OR⁸, —S(═O)₂R⁸, —C(═O)NR⁶R⁷,C₁-C₄-alkyl-, and C₃-C₅-cycloalkyl-, wherein said C₁-C₄-alkyl- orC₃-C₅-cycloalkyl-group is optionally substituted with one substituentselected from the group consisting of fluorine, hydroxy, cyano,C₁-C₃-alkoxy-, —NH₂, alkylamino-, dialkylamino-, and cyclic amines; R⁶and R⁷ are independently a group selected from the group consisting of ahydrogen atom, C₁-C₄-alkyl- and C₃-C₅-cycloalkyl-, wherein saidC₁-C₄-alkyl- or C₃-C₅-cycloalkyl-group is optionally substituted withone or two substituents, identically or differently, selected from thegroup consisting of hydroxy, C₁-C₂-alkyl-, C₁-C₂-alkoxy-, —NH₂,alkylamino-, dialkylamino-, and cyclic amines; or R⁶ and R⁷ are takentogether with the nitrogen atom to which they are attached to form acyclic amine; and R⁸ is a group selected from the group consisting ofC₁-C₆-alkyl-, fluoro-C₁-C₃-alkyl-, C₃-C₅-cycloalkyl- and phenyl-,wherein said group is optionally substituted with one substituentselected from the group consisting of halogen, hydroxy, C₁-C₂-alkyl-,C₁-C₂-alkoxy-, and —NH₂, or an enantiomer, a diastereomer, apharmaceutically acceptable salt, or a solvate thereof, or apharmaceutically acceptable salt of said solvate.
 3. The compound offormula (I) according to claim 1, wherein: L is a C₂-C₄-alkylene group;X and Y are CH or N with the proviso that one of X and Y is CH and oneof X and Y is N; R¹ is a C₁-C₄-alkyl-group, wherein said group isoptionally substituted with one or two substituents, identically ordifferently, selected from the group consisting of hydroxy,C₁-C₂-alkoxy-, —NH₂, and —C(═O)OH; R² is a hydrogen atom or a cyanogroup; R³ is a group selected from the group consisting of a hydrogenatom, a fluorine atom and a methoxy-group; R⁴ is a group selected fromthe group consisting of a hydrogen atom and a fluorine atom; and R⁵ is agroup selected from the group consisting of a hydrogen atom, cyano,C₁-C₄-alkyl-, and C₃-C₅-cycloalkyl-, wherein said C₁-C₄-alkyl-group isoptionally substituted with one hydroxy group, or an enantiomer, adiastereomer, a pharmaceutically acceptable salt, or a solvate thereof,or a pharmaceutically acceptable salt of said solvate.
 4. The compoundof formula (I) according to claim 1, wherein: L is a C₃-C₄-alkylenegroup; X and Y are CH or N with the proviso that one of X and Y is CHand one of X and Y is N; R¹ is a methyl-group; R² is a hydrogen atom ora cyano group; R³ is a fluorine atom; R⁴ is a group selected from thegroup consisting of a hydrogen atom and a fluorine atom; and R⁵ is agroup selected from the group consisting of a hydrogen atom, cyano,C₁-C₃-alkyl-, and cyclopropyl-, wherein said C₁-C₃-alkyl-group isoptionally substituted with one hydroxy group, or an enantiomer, adiastereomer, a pharmaceutically acceptable salt, or a solvate thereof,or a pharmaceutically acceptable salt of said solvate.
 5. The compoundof formula (I) according to claim 1, wherein: R² is a hydrogen atom or acyano group, or an enantiomer, a diastereomer, a pharmaceuticallyacceptable salt, or a solvate thereof, or a pharmaceutically acceptablesalt of said solvate.
 6. The compound of formula (I) according to claim1, wherein: R³ is a fluorine atom; and R⁴ is a hydrogen atom, or anenantiomer, a diastereomer, a pharmaceutically acceptable salt, or asolvate thereof, or a pharmaceutically acceptable salt of said solvate.7. The compound of formula (I) according to claim 1, wherein: L is a—CH₂CH₂CH₂— or a —CH₂CH₂CH₂CH₂— group; X and Y are CH or N with theproviso that one of X and Y is CH and one of X and Y is N; R¹ is amethyl-group; R² is a hydrogen atom or a cyano group; R³ is a fluorineatom; R⁴ is a hydrogen atom or a fluorine atom; and R⁵ is a groupselected from the group consisting of a hydrogen atom, cyano, methyl-,3-hydroxypropyl- and cyclopropyl-, or an enantiomer, a diastereomer, apharmaceutically acceptable salt, or a solvate thereof, or apharmaceutically acceptable salt of said solvate.
 8. The compoundaccording to claim 1, which is selected from the group consisting of:15,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine;(rac)-3-(2-{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}-2-methyl-2λ6-diazathia-1,2-dien-1-yl)propan-1-ol;(rac)-[{[15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecin-8-yl]methyl}(imino)methyl-λ6-sulfanylidene]cyanamide;(rac)-8-[(N,S-dimethylsulfonodiimidoyl)methyl]-15,19-difluoro-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine;16,20-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;16,20,21-trifluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;16,21-difluoro-9-[(S-methylsulfonodiimidoyl)methyl]-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;15,19-difluoro-8-[(S-methylsulfonodiimidoyl)methyl]-3,4-dihydro-2H,11H-10,6-(azeno)-12,16-(metheno)-1,5,11,13-benzodioxadiazacyclooctadecine-7-carbonitrile;(rac)-9-[(N-cyclopropyl-S-methylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine;and(rac)-9-[(N,S-dimethylsulfonodiimidoyl)methyl]-16,20-difluoro-2,3,4,5-tetrahydro-12H-13,17-(azeno)-11,7-(metheno)-1,6,12,14-benzodioxadiazacyclononadecine,or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, ora solvate thereof, or a pharmaceutically acceptable salt of saidsolvate.
 9. A method for treating lung carcinomas, prostate carcinomas,cervical carcinomas, colorectal carcinomas, melanomas, ovariancarcinomas or leukemias in a subject in need thereof, comprisingadministering a therapeutically effective amount of the compound offormula (I) according to claim 1, or an enantiomer, a diastereomer, apharmaceutically acceptable salt, or a solvate thereof, or apharmaceutically acceptable salt of said solvate, to the subject.
 10. Amethod for treating non-small cell lung carcinomas, hormone-independenthuman prostate carcinomas, multidrug-resistant human cervical carcinomasor human acute myeloid leukemias in a subject in need thereof,comprising administering a therapeutically effective amount of thecompound of formula (I) according to claim 1, or an enantiomer, adiastereomer, a pharmaceutically acceptable salt, or a solvate thereof,or a pharmaceutically acceptable salt of said solvate, to the subject.11. A pharmaceutical composition comprising the compound according toclaim 1, or an enantiomer, a diastereomer, a pharmaceutically acceptablesalt, or a solvate thereof, or a pharmaceutically acceptable salt ofsaid solvate, in combination with an inert, nontoxic, pharmaceuticallysuitable adjuvant.
 12. A method for treating lung carcinomas, prostatecarcinomas, cervical carcinomas, colorectal carcinomas, melanomas,ovarian carcinomas or leukemias in a subject in need thereof, comprisingadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 11 the subject.
 13. A process for preparing acompound of formula (10)

wherein R¹, R², R³, R⁴, R⁵ and L are as defined for the compound offormula (I) according to claim 1, comprising: reacting a compound offormula (9)

wherein R¹, R², R³, R⁴ and L are as defined for the compound of formula(I) according to claim 1, with an oxidizing agent selected from thegroup consisting of iodobenzene diacetate and N-chloro succinimide,followed by a primary amine of formula R⁵—NH₂, wherein R⁵ is as definedfor the compound of formula (I) according to claim 1, orhexamethyldisilazene to give the compound of formula (10), andoptionally, if appropriate, reacting the compound of formula (10) with(i) a solvent and/or (ii) a base or acid to give the solvate orpharmaceutically acceptable salt thereof and/or the pharmaceuticallyacceptable salt of said solvate.
 14. A process for preparing a compoundof formula (23)

wherein R¹, R², R³, R⁴, R⁵ and L are as defined for the compound offormula (I) according to claim 1, comprising: reacting a compound offormula (22)

wherein R¹, R², R³, R⁴ and L are as defined for the compound of formula(I) according to claim 1, with an oxidizing agent selected from thegroup consisting of iodobenzene diacetate and N-chloro succinimide,followed by adding a primary amine of formula R⁵—NH₂, wherein R⁵ is asdefined for the compound of formula (I) according to claim 1, orhexamethyldisilazene to give the compound of formula (23), andoptionally, if appropriate, reacting the compound of formula (23) with(i) a solvent and/or (ii) a base or acid to give the solvate orpharmaceutically acceptable salt thereof and/or the pharmaceuticallyacceptable salt of said solvate.
 15. The compound of claim 1, apharmaceutically acceptable salt thereof.
 16. The compound of claim 8 apharmaceutically acceptable salt thereof.
 17. The pharmaceuticalcomposition of claim 11, comprising the compound of formula (I) or apharmaceutically acceptable salt thereof.